Though we concentrate our research and program efforts on Asthma, COPD, Lung Cancer, Infectious Respiratory Disease, and Smoking/Vaping Cessation, we also fund the research projects of some young investigators beyond our usual focus areas to promote talent in the field and to advance our understanding on all lung issues.
General Lung Disease Research Projects
Dr. Golnaz Karoubi
3D Biomimetic Culture System for Study of Alveolar Epithelial Cells epithelial cells
Lung injury and disease continue to be important clinical problems and major health care burdens. Injury, for example from viruses, are highly variable, and can result in respiratory failure and death; an unfortunate reality such as we have observed with the COVID19 coronavirus. A major limitation is incomplete knowledge of the mechanism of disease. A complete understanding of how cells of the airway are affected and how the disease progresses will allow us to develop new therapies that effectively eliminate or prevent disease. To gain a better understanding of disease, we need to ex vivo (outside of the body) models of airway epithelial cells. Ideally, one can imagine taking primary airway cells from patients or use airway cells obtained from patient stem cells and growing them in the lab. But to successfully culture and grow airway cells ex vivo, we need the right chemical and mechanical environment.
Existing models of airway epithelial cells do not take into consideration the geometry and mechanical environment that airway cells are exposed to. The alveolus, for example, where breathing takes place, is a very dynamic environment with cycles of the alveolus expanding and contracting during the process of breathing. The objective of our project is to grow human primary airway cells and airway cells derived from stem cells ex vivo, in our unique platform which mimics the conditions airway cells would be exposed to in the body. We have named this platform ‘biomimetic alveoli’. In our system, airway cells are grown in ‘dimples’ that are the same size and geometry of the alveoli in human lungs. Additionally, our ‘biomimetic alveoli’ can mimic the breathing movement of human lung alveoli so that the cells can experience the physical forces of repeated cycles of stretch. Using our ‘biomimetic alveoli’, we will ask the following questions: (1) Do alveolar airway epithelial cells grow and behave as they do in the human body? and (2) Can we use the ‘biomimetic alveoli’ to model lung injury?
To answer our questions we will isolate airway epithelial cells from healthy human tissue using techniques we have established in the lab. We will also obtain airway epithelial cells from human induced pluripotent stem cells. These cells will be placed in our ‘biomimetic alveoli’ system. The ‘biomimetic alveoli’ is made using a cylindrical chamber containing a very thin silicone membrane which is placed on top of a stainless steel disk with holes (of the same diameter as a human alveolus). The chamber is then connected to a pressure system which acts via negative pressure to pull down the membrane creating semi-spherical ‘dimples’. The pressure system then oscillates between different pressures that would be seen in healthy human lungs to create an expansion/contraction movement similar to breathing.
What is unique about our project is that we present (1) a three dimensional electro-pneumatically controlled ‘biomimetic alveolus’ platform which captures the environment that airway epithelial cells sense in the human body; (2) a physiologically relevant model of ventilator induced lung injury (VILI); and (3) the use of human pluripotent derived airway epithelial cells for modelling healthy and diseased lung.
The impact of our work is directly relevant to the lung health of Canadians. Our ‘biomimetic alveolus’ will allow relevant models of the airway in health and disease. Modelling of healthy alveolar epithelial cells will improve our understanding of these cells and the impact of environmental factors, injury conditions, and pathogens such as viruses. Importantly, modelling of alveolar epithelial cells from patients or derived from stem cell lines of patients will allow future development and testing of therapeutics.
Dr. Lisa Wickerson
Clinical utility of remote walk tests in advanced lung disease
Exercise is an important part of the care in people with lung disease, and participation in a rehabilitation program is recommended to improve walking endurance, muscle strength, symptoms of shortness of breath and quality of life. To be effective and safe, exercise training such as walking should be guided by an exercise walking test. Walking tests also provide important information on how people are tolerating their exercise and/or if their physical condition is worsening. Walk tests have traditionally been performed in-person at a healthcare centre.
The COVID-19 pandemic has restricted outpatient visits to healthcare centres for infection control purposes. There is uncertainty on how to perform walking tests in the home setting as standardized tests require a long, unobstructed corridor. High quality medical monitors that measure oxygen levels and heart rate may not be available. However the ability to perform walk tests in the home will allow healthcare providers to perform tests by video which may be more convenient for patients and support infection control practices.
This project will examine two common walk tests: the 6-minute walk test and the incremental shuttle walk test. We will compare the distance walked during tests under different testing conditions (indoor hallway of different lengths and on a treadmill) and settings (in a healthcare centre and at home). We will also examine how people tolerate these different testing conditions in terms of oxygen levels, heart rate, symptoms of shortness as well as test preference. We will also examine how well a home-based test can guide a home walking program.
We will recruit people with chronic lung disease who are listed for lung transplantation and regularly undergo walk tests and participate in exercise training. Participants will perform the walk tests at the healthcare centre followed by walk tests at home supervised and guided by a physiotherapist using video.
The COVID-19 pandemic has changed the way people with lung disease participate in a rehabilitation program, moving more exercise sessions into the home. Little is known about the usefulness of remote walk tests. This project will also look at two different walk tests.
A home walking program that is done at the right level of exercise will lead to better functioning of the individual. Home walk tests may be able to be performed more regularly allowing healthcare professionals to keep a closer eye on the home program. It may lead to less on-site visits and travel for patients.
Differentiate between IPF and CPFE using Respiratory Oscillometry
Idiopathic pulmonary fibrosis (IPF) is one of the most common diagnosed form of Interstitial Lung Disease (ILD). The degree of lung fibrosis is often correlated with reduction in lung compliance. Combined pulmonary fibrosis and emphysema (CPFE) is another form of ILD that can be challenging to diagnose as the reticulation admixed with emphysema may be described as honeycombing. Conventional pulmonary function tests (PFT) with spirometry are insensitive to small airways dysfunction and provide us with limited information of lung compliance and airway resistance. Respiratory oscillometry (Osc) measures total respiratory impedance (Z), composed of resistance (R) and reactance (X) allowing us to measure dynamic lung compliance.
Use respiratory oscillometry to differentiate between idiopathic pulmonary fibrosis and combined pulmonary fibrosis and emphysema Methods: IPF and CPFE patients who were clinically identified by the ILD clinic were prospectively enrolled and assessed with paired Osc-PFT.
A total of 173 participants were enrolled from September 2019 to April 2021. Of the 173, 153 participants belonged to the IPF only group and 20 in the CPFE group. For IPF group, X5 and X5in demonstrated strong correlation with FVC, FEV1, TLC and DLCO. AX and Fres also demonstrated strong correlation with FVC and FEV1 in the IPF group. In contrast with the CPFE group, R5in-ex. showed strong correlation with %RV/TLC, RV/TLC and DLCO. Moderate correlations were seen between AX and Fres with FVC in the IPF group. Whereas in the CPFE group, moderate correlations were observed between R5in, X5in, R5-19ex, and FEV1/FVC. Additionally, X5in and R5-19ex moderately correlated with TLC in the CPFE group.
Respiratory oscillometry can be a pulmonary function diagnostic tool added as an adjunct to conventional PFTs to aid in differentiation between IPF and CPFE to help patient care and diagnosis.
Dr. Mauricio Terebiznik
Asbestos Phagocytosis by Alveolar Macrophages: Disruption of Phagosomal Morphogenesis and Function
Asbestos is a fibrous mineral that due to its fire-resistant and insulating properties, has been widely used in the fabrication of a large variety of products and materials. However, asbestos releases respirable fibers that have been linked to the development of many respiratory diseases, including chronic lung inflammation and lung cancer. For this reason, asbestos was declared an occupational carcinogen and its production and commercialization banned in several countries. Nevertheless, asbestos still remains in residues from mining activity, construction material, military equipment, and thousands of other different products worldwide. Thus, asbestos continues to be a public health burden. Asbestos fibers cause disease once inhaled and deposited in the lung. Differently from other materials that enter the lung, asbestos cannot be cleared by macrophages, the housekeeping cells that clean the tissue from foreign particles and microbes. Instead, asbestos causes macrophages to trigger a strong inflammatory response, which damages the lung. This damage leads to asbestos-related diseases.
The objective of this project is to understand the mechanism by which asbestos impedes the functioning of macrophages and harms the lung. We will investigate how the fiber length and chemical properties of asbestos impact the function of macrophages, and how to reverse these effects.
We will utilize state of the art microscopy technologies combined with molecular and cellular techniques to visualize the fate of asbestos inside lung macrophages. We will develop techniques to label and track asbestos fibers inside lung-derived macrophages to detect and quantify any damage sustained by cellular organelles. We will explore different ways of protecting macrophages from the toxic effect of asbestos.
Previous works have focused only on the length of asbestos fibers as the determining factor causing macrophage dysfunction and thus asbestos-related disease. Utilizing powerful microscopes to visualize asbestos inside macrophage cells, and their interactions with organelles and the plasma membrane, our approach will identify contributing factors besides length of the fiber in the disruption of macrophage function.
Exposure to asbestos is one of the primary causes of workplace-related fatalities in Canada. Since 1996, asbestos-related diseases caused around a third of workplace deaths. In Canada, which had dominated the global asbestos production and commercialization markets until its recent prohibition in 2018, the exposure to asbestos remains one of the leading causes of occupational death. A better understanding of the cellular mechanisms by which asbestos persists in the lung and causes disease will foster opportunities in diagnostic and therapeutic interventions promoting lung health in the affected individuals.
Dr. Kjetil Ask
Investigating the Role of Myeloid-derived Macrophages in Fibrotic Lung Disease
Lung fibrosis is a disease that often proves fatal 2-3 years post-diagnosis. It affects about 15,000 Canadians with approximately 6,000 new diagnoses made each year. As the disease progresses, scar tissue accumulates in the lungs, making breathing difficult and then impossible. There are few treatment options for this type of disease. The reason for this is likely because we do not know well how people develop the disease in the first place and we know very little about how and why the scarring is out of control. If we can better understand which cells are responsible for making the scars and how they produce the scars, then we may be able to stop the scarring process so patients can breathe better and live longer.
Our project aims to understand the molecular processes leading to the generation of a specialized cell type called the macrophage. We think that under certain circumstances, macrophages are very important in the scarring process and that they contribute to the formation of the scars in the lungs. Our main objective is to provide scientific evidence that they are truly involved and required for the scarring process, and to better understand how they do it. If we can increase our understanding of the molecular mechanisms driving this process and demonstrate that this cell is critical for the scarring process, then we can perhaps stop the scarring process and help patients to breathe better and improve their quality of life.
We have already identified a key molecular mechanism and what we think is the most important cell – the macrophage. We have also identified a unique marker of this important cell. Here, we will continue this work and clarify if the unique marker is also actively involved in the fibrotic process. By examining the specific role of this molecule, we believe we can identify a novel therapeutic target required in the scarring process.
Our project is unique because we are exploring a molecular mechanism that is well-known in other cell types but that has never been shown to be important in macrophages or in lung fibrosis.
Our research will help to further understand the role of activated macrophages in pulmonary fibrosis. Though our projects described in this application are focused on lung fibrosis, these mechanisms are likely to have similarities with those in other chronic lung diseases that have components of scarring associated with their disease such as asthma (airway fibrosis) and COPD (bronchial fibrosis). If we can further our understanding on how macrophages contribute to the scarring process and if they are essential for this process, we can perhaps find new treatment options for patients with fibrotic lung disorders.
Dr. Ruud Veldhuizen
Anti-inflammatory Exogenous Surfactant for ARDS
Our lab studies a condition call Acute Respiratory Distress Syndrome (ARDS) which is defined by severe lung dysfunction which presents itself as reduced amounts of oxygen being transported by the blood. Although many clinical trials have been performed on a variety of drugs, no pharmacological treatment has been proven to be efficacious in patients with this syndrome. We propose that one of the reasons for the lack of success in the clinical trials is not because the drugs themselves are not effective but rather, is due to the drugs not reaching the area of the lung where they are required to provide a therapeutic benefit. This hurdle in effective treatment is related to the complex branching structure of the lung which makes it difficult to get drugs to the injured regions of the lung.
Our proposal addresses this issue by specifically testing one drug, the anti-inflammatory agent Budesonide, using a novel method of delivery method, exogenous surfactant, as a carrier to ensure optimal pulmonary delivery. As such we will test the hypothesis that: BLES + Budosonide improves outcomes in ARDS.
Our hypothesis will be tested in two objectives: Objective 1) laboratory studies optimizing surfactant + Budesonide combinations to produce an effective new therapeutic. Objective 2) Animal studies testing the efficacy of surfactant + Budesonide as a therapy for ARDS.
We will utilize a new methodology, the so-called wet bridge transfer method, developed in our lab to test various combination of our delivery vehicle with the drug in the laboratory setting. Subsequently, we will use a rat model of ARDS to test if this new therapeutic approach can improve outcomes in the disease. Q17 d) What is unique/innovative about your project? ARDS is a significant health issue in terms of patient numbers, mortality, and health care cost. The experiments proposed may provide a new therapeutic approach for ARDS by improving the delivery of an existing drug.
Our proposal focuses on ARDS, which is a pulmonary condition with a high mortality rate and for which no effective therapeutics are available. Our studies may ultimately contribute to the design of clinical trials testing our new therapeutic approaches for this disease.
Dr. Sean Gill
The Role of Extracellular Matrix-Pulmonary Microvascular Endothelial Cell Interaction in Regulation of Microvascular Permeability during Lung Injury
Acute respiratory distress syndrome (ARDS) is a common and serious lung condition that affects 10,000 Canadians every year and is fatal in 40% of patients. There are many causes of ARDS, which most commonly occurs following a widespread (throughout the body) infection called sepsis. ARDS is characterized by (i) severe lung inflammation and (ii) the leak of fluid and protein from the blood vessels into the airspaces within the lung, leading to fluid-filled lungs and severe respiratory failure. This fluid leak occurs due to injury of the blood vessels of the lungs, especially the cells that line the inside, or endothelial cells (EC). There is no current treatment for the severe lung inflammation and fluid leak in patients with ARDS.
Our research focuses on understanding how fluid and protein leak from the blood vessels into the airspaces of the lung. In healthy people, EC form a barrier by interacting with neighbouring EC through special proteins, such as the protein vascular endothelial (VE)- cadherin, as well as by interacting with a scaffold that is found under the EC called the extracellular matrix. Recently, we discovered that if EC cannot bind to the scaffold, they have difficulty forming a barrier and this leads to increased leak. This impaired ability to bind the scaffold appears to be controlled by enzymes made by the EC, known as metalloproteinases. How these enzymes cause this impaired binding to the scaffold is not currently known. We will examine how metalloproteinases control EC binding to the matrix during both health and injury/infection.
We will study EC isolated from the lungs of mice and humans, grow them in vitro (in test tubes), and expose them to chemicals that cause inflammation and damage like in ARDS. Importantly, we will isolate EC from normal mice as well as mice lacking specific proteins that control the activity of the metalloproteinases, which leads to excessive enzyme activity and breakdown of the scaffold. We also treat the EC with chemicals (drugs) that block the action of the metalloproteinases to further examine their contribution to EC damage and leak. Finally, we will use a special technique called TAILS that will enable us to identify all of the proteins from the EC and from the scaffold that are cleaved or broken down by metalloproteinases.
This project is innovative in the following ways: 1) identification of a new mechanism (metalloproteinases) causing loss of EC interaction with the scaffold (matrix) and EC fluid/protein leak; 2) study of EC damage and fluid/protein leak in human lung EC, which is of direct relevance to human patients with sepsis/ARDS; and 3) use of TAILS to comprehensively assess scaffold protein degradation.
Our studies will help us understand how fluid and protein leak from blood vessels into the airspaces of the lungs in ARDS, and may provide information regarding future novel therapeutic approaches. New medications to treat patients with sepsis/ARDS would potentially decrease death following ARDS. Importantly, many patients survive ARDS, but most have ongoing difficulties such as shortness of breath and reduced quality of life. New therapies for ARDS could decrease lung damage and improve lung function, leading to enhanced quality of life for patients that survive ARDS.
Dr. Gaspard Montandon
Identification of New Molecular Pathways Regulating Opioid-induced Respiratory Depression and Safe Opioid Pain Therapies using Zebrafish Models
A serious opioid epidemic is currently spreading in North America. Overdoses due to opioids, such as oxycodone and fentanyl, are responsible of over 30,000 deaths per year. Opioid overdose is not only due to street drug abuse like heroine but also to misuse of prescription pain killers. In addition to their intended, analgesic effects, these medications stop breathing and induce hypoxemia, and there are no treatments to prevent respiratory depression without reducing their analgesic properties. In fact, the opioid antagonist naloxone or Narcan blocks the opioid side-effects, but it also blocks analgesia so cannot be used as an adjunct treatment to prevent respiratory depression. The development of therapies has been hindered by the lack of understanding of the mechanisms of respiratory depression by opioids. We propose novel and unique gene and drug screening approaches allowing us to identify the genes regulating opioid inhibition and to find potent analgesic therapies without the side-effects of respiratory depression. Without safe pain treatments, opioids will continue to present severe health issues, and the death toll associated with opioid overdose will continue to rise.
Here we propose a paradigm shift in the development of safe opioid therapies. To this aim, we propose to target the mechanisms underlying respiratory depression and to determine whether they also mediate opioid analgesia. Using this knowledge, we aim to find an adjunct medication that can be added to opioid formulations and to block respiratory depression, without blocking analgesia, therefore allowing the use of existing potent opioid analgesics.
Our program combines gene and drug screening approaches and behavioral profiling in zebrafish to identify novel therapies to prevent respiratory depression without compromising opioid analgesia. Larval zebrafish are amenable animal models for drug discovery because of high production of embryos, external fertilization which facilitates gene editing, and transparency which allows brain imaging. We have developed models of respiratory depression and analgesia by opioid drugs, which can be easily used to test new candidate genes and novel drug compounds.
Using unique zebrafish models, we propose to identify the genes regulating respiratory depression by opioids, so new therapies can be developed to prevent it. We are currently the only research team performing opioid research and drug screening in larval zebrafish.
Overdose by opioid drugs induces severe respiratory depression and may lead to hypoxemia and death. By funding this research, the OLA would support an innovative and unique research program that is critical to Canadians’ health. Identification of new drugs will lead to therapeutic strategies combining potent analgesia with reduced respiratory side-effects, so patients can receive safe pain therapy.
Dr. Chung-Wai Chow
Airway Oscillometry for Early Detection of Allograft Dysfunction Following Lung Transplant
Lung transplantation (LTx) has significantly improved survival and quality of life for patients with endstage lung diseases. However, long-term survival lags behind other solid organ transplants, and is primarily due to development of chronic lung allograft dysfunction (CLAD). CLAD develops in 50% of all LTx recipients by year 5 and is the major cause of death by 5 years post-LTx. CLAD is defined as an irreversible drop in the forced expiratory volume in 1 sec (FEV1) and/or forced vital capacity (FVC) of ≥ 20% from the best baseline value attained following LTx. It is a diagnosis of exclusion that is made retrospectively when other causes of a decline in lung function have been ruled out. No treatment is available for CLAD. This may be a result of the manner in which CLAD is defined i.e. by the time a diagnosis is made, tissue injury to the graft is already well established and cannot be reversed.
Compounding the retrospective nature of CLAD diagnosis is the insensitivity of spirometry for detection of small airway function. FEV1 is largely sensitive to central airway obstruction and remains unchanged until 75% of all the small airways are occluded. Yet, the primary sites of injury of CLAD is the small airways and the lung periphery. If it is possible to identify CLAD early, there is a possibility for early intervention. In order to do so, we need to find diagnostic tools that can evaluate small airway function accurately.
Airway oscillometry (Osc) is a simple pulmonary function test (PFT) that directly assesses small airways. It has been found to detect lung function changes earlier than spirometry in chronic obstructive lung disease and be a better metric of asthma control. Our group has an ongoing prospective study in newly transplanted LTx recipients (funded by the Lung Association). Our preliminary data found Osc to detect acute allograft rejection (another graft insult that occurs in the small airways) earlier spirometry. The role of Osc in detecting CLAD and the Osc measurements of CLAD are not known.
The goal of the current study is to characterize the Osc measurements of patients with established CLAD. Once we have established the Osc values that define CLAD, we intend to apply these measurements to the ongoing prospective study to determine if Osc can predict the develop of CLAD. If Osc can predict early CLAD, future studies can use Osc as a tool to monitor the effect of interventions that are focused on treatment of CLAD.
This is a cross-sectional study that will enroll 50 double LTx patients who are ≥2 ] years post-LTx and who have established CLAD. Single LTx recipients will be excluded. Our program transplants >200 patients per year and follows patients for life (currently >1000). Thus, it is possible to enroll 50 CLAD patients.
Our power calculations determined that 124 CLAD and 124 CLAD-free patients are needed to identify the diagnostic cut-off values of Osc that can discriminate CLAD vs CLAD-free with 90% sensitivity and 90% specificity. We are constrained by the funding envelope of $50,000 to studying only 50 CLAD patients although our patient population has the capacity to enroll 124 CLAD patients. We will therefore use the pilot data to leverage further funding enroll the additional CLAD patients needed.
A group of CLAD-free patients who have been followed for ≥1 year in our ongoing prospective study and who are CLAD-free will be used for comparison. Patients beyond 1 year post-LTx are used as controls because FEV1 and FVC improve over time and plateau at 1 year so that most patients achieve their best lung function post-LTx at 1 year. Our prospective study already enrolled 187 patients by June 30, 2019; they will have at least 1 year of follow-up when the current project begins in July 2020. Thus, we will have data for >150 CLAD-free patients.
Osc will be conducted during the same visit as the conventional PFT. All LTx patients followed at our centre annually for life with clinical visits, bloodwork and PFT. Computed tomography (CT) imaging of the lung is done up to 2 years post-LTx. For this study, we will perform an additional study-related CT inspiration-expiration exam to conduct quantitative measurements small airway diseases.
This is the first study to characterize Osc measurements in CLAD and to correlate these physiologic metrics with quantitative measurement of small airway disease using CT imaging. No other program in the world has the patient population nor expertise to conduct this study.
Data garnered in the current project will support a follow-up study to validate the predictive value of Osc in detecting CLAD. Once we have validated measurements for the early detection of CLAD, we can apply these to monitor therapies to prevent development of CLAD and improve long-term survival post-LTx. Our findings will add to the growing body of evidence that Osc is an early warning detection system of airway dysfunction, regardless of etiology. Thus, Osc for monitoring of obstructive and possibly restrictive lung diseases are readily translated to other patient populations. In other words, Osc could lead to improvements in respiratory health for all Canadians.
Dr. Laurent Brochard
Correlation Between Sleep-Wakefulness Continuum, Sedation and Patient-Ventilator Asynchronies
Many patients in the intensive care unit (ICU) require mechanical ventilation (MV). This is a life-saving treatment but it still presents complications and high mortality. Among these complications, patients often experience sleep deprivation, decreased brain function and psychological distress. We have accumulative evidence that poor interaction between patients and their ventilators (called “asynchrony”) is associated with increased duration of MV and mortality. Asynchrony also contributes to sleep deprivation, leading to temporary cessation of breathing, awakenings and arousal during sleep, or to discomfort that stops patients from falling asleep or reaching deep sleep. Some patients look awake but have decreased brain activity defined as pathological wakefulness. This state is associated with delirium, cognitive and psychological impairment. The Odds ratio product (ORP), is a new, continuous, automatic measure of sleep depth using simplified electroencephalogram (EEG). ORP could identify pathological wakefulness and quantify its severity. The exact relationship between pathological wakefulness, quality of sleep, sedation and asynchrony is unknown.
The primary aim will be to determine in patients on mechanical ventilation the frequency of asynchronies and corresponding range of ORP for each type of asynchrony. The secondary aims will include a) evaluation of the presence and duration of pathological wakefulness, b) duration and daily distribution of different ranges of ORP (sleep depth), c) correlation between time spent at different ranges of ORP and cumulative doses of sedative agents, and d) correlation between the presence of pathological wakefulness and duration of mechanical ventilation.
This will be an observational cohort study included as an ancillary analysis of the largest international study that aims at understanding the mechanisms and consequences of asynchronies under mechanical ventilation (the BEARDS study clinicaltrials.gov #NCT03447288), adding continuous EEG measurements to the measurement of asynchronies. We will include patients with moderate and severe acute hypoxemic respiratory failure under deep sedation at inclusion and we will perform continuous recordings of respiratory waveforms and electroencephalogram (EEG) from intubation and up seven days in alternate days. Additionally, data on sedative agents, behavioral response and other clinical variables will be collected at baseline and hourly during the study period. Outcome data will include duration of mechanical ventilation amongst other.
Automatic analysis of the waveforms and EEG will be performed using validated softwares to diagnose asynchronies (in respiratory waveforms) and quantify ORP (EEG). Then, presence of asynchronies will be correlated with the value of ORP (corresponding to the level of brain activity within the range of sleep-wakefulness continuum).
Additionally, ORP will be correlated with doses of sedative drugs. Finally, the presence of pathological wakefulness will be defined when patients are behaviorally awake (they “look” awake as defined by sedation scores) but display an ORP consistent with not being “fully” awake. The presence of pathological wakefulness will be correlated with duration of mechanical ventilation. we will add a continuous measure of EEG which measures the electrical activity of the brain.
This research is unique as 1) No similar studies have been undertaken. 2) There is currently no conventional sleep scoring tool due to the challenging nature and feasibility in ICU patients. Linking asynchrony with ORP values should allow to have a new detection tool helping to implement strategies to 1) decrease asynchrony, 2) improve sleep and prevent pathological wakefulness.
More than 40,000 Canadians receive mechanical ventilation in the ICU every year. A better understanding of the determinants of prolonged mechanical ventilation is crucial to preventing the long-term complications of mechanical ventilation. This study will determine the relationship between pathological wakefulness, asynchronies and sleep, and their association with outcomes. This will then allow future interventional study aiming at controlling these factors in order to reduce complications of mechanical ventilation, improving patient´s lung and overall health.
Dr. Indra Narang
The Use of Heated High Flow Nasal Cannula Therapy for the Management of Obstructive Sleep Apnea in Obese Adolescents
In Canada, adolescents are increasingly diagnosed with persistent sleep apnea due to the obesity epidemic. Currently, 1 out of 7 adolescents are obese and 25-60% of obese adolescents will develop sleep apnea. Sleep apnea, diagnosed using a sleep study test, occurs when there is a temporary blockage of the airway during sleep, causing oxygen levels to fall as well as sleep disturbance and related daytime sleepiness. Of great concerns is that sleep apnea is untreated in more than 50% of obese adolescents as they are not able to use continuous positive airway pressure (CPAP). CPAP is the current standard of care therapy for persistent sleep apnea that delivers pressured air via a tight-fitting mask to keep the airway open. CPAP is highly effective when used on a nightly basis but must be worn for many years into adulthood. Of most concern, untreated sleep apnea is associated with long-term health problems including poor quality of life, anxiety and depression, diabetes and a 3-7 times increased risk for motor vehicle collisions as well as poorer academic performance. Novel alternative and effective therapies are urgently needed to treat sleep apnea. One such potential therapy is heated high flow air nasal cannula (HFNC), which delivers warm and humidified air at high flow rates through the nose and may relieve sleep apnea.
HFNC is currently used in hospitals to help patients with respiratory infections or lung diseases. HFNC delivers pressured air, which is warm and humidified, using a soft, loose fitting nasal tube known as a cannula, making it comfortable and better-tolerated. However, HFNC has not been well tested in patients with sleep apnea and further research is needed to assess its effectiveness for treating sleep apnea. The objective of this study is to test HFNC therapy in obese adolescents with sleep apnea and see if it improves their sleep apnea and is comfortable when compared to CPAP.
Obese children diagnosed with sleep apnea usually attend our sleep clinic at the Hospital for Sick Children, Toronto. We will ask adolescents to have 2 sleep study tests on separate nights, one with CPAP and one with HFNC, which will be done in a random order. We will compare the results of HFNC with CPAP to see if HFNC is just as effective in treating sleep apnea. Subjects will also report their level of comfort with CPAP and HFNC.
CPAP is the main treatment for obese adolescents with sleep apnea and over the last 20 years, there has not been any new, effective therapies for treating sleep apnea in children. HFNC is a promising new therapy as it is comfortable and well-tolerated, and may have the potential to significantly change how we successfully treat sleep apnea, yielding significant health benefits.
Sleep apnea is very common in obese children. As physicians, we can no longer ignore the issue that sleep apnea is undertreated or untreated because CPAP is uncomfortable for a significant number of children. To improve the health of children with sleep apnea, we have to be very proactive in our search for alternative treatments. If HFNC is an effective therapy for sleep apnea, HFNC will lead to short term benefits such as improved sleep and school performance but will also be associated with improving the overall health of Canadian children as they enter adulthood.
Dr. Tetyana Kendzerska
Air Pollution and Control of Obstructive Sleep Apnea by Positive Airway Pressure Therapy
We propose to determine if outdoor air pollution adversely affects adults with OSA who are using PAP utilizing linked clinical, weather and air pollution databases. Specifically, as a primary research objective, we will assess if outdoor air pollution affects OSA control on PAP treatment as measured by residuals respiratory events and required pressure level to control OSA (a surrogate of worse upper airway anatomy). As a secondary objective, we will evaluate if air pollution affects PAP adherence. We hypothesize that greater air pollution is associated with worse control of OSA on PAP and reduced adherence with PAP.
All consented adults diagnosed with OSA who purchased a PAP device from the vendor registered with the Assistive Device Program (Ottawa, Ontario) between 2011 and 2017 and whose data on PAP adherence and OSA control since PAP purchase was transferred from their devices will be considered for inclusion (n~10,000). Detailed daily stamped information on PAP settings and mode, time on therapy, optimal pressure level and the control of SDB are available for included individuals. Using the 6-digit postal code, we will link data on PAP usage and SDB control with the Air Quality Data Sets (2000-2017). Subjects will be assigned the air pollution values obtained from the National Air Pollution monitor closest to their neighborhood. Daily ambient air pollution data will be provided by the National Air Pollution Surveillance System. Daily meteorological data will be obtained from the National Climate Data and Information Archive. Monitored air pollutants of interest will be ground-level ozone, fine particulate matter (PM2.5), nitrogen dioxide and sulfur dioxide. This information will also be used to calculate the Air Quality Health Index. Weather variables derived will be daily temperature and relative humidity. We will utilize complex analytical approaches to assess the acute and cumulative effects of air pollution.
In our study, we will be able to investigate if outdoor air pollution adversely affects OSA in individuals who are using PAP, which have not previously been addressed. We are uniquely positioned to investigate this relationship, as we have access to daily PAP usage and daily air pollution data. Ontario continues to benefit from one of the most comprehensive air monitoring systems in North America, comprised of 39 monitoring sites across the province that undergo regularly scheduled maintenance and strict data quality assurance and quality control procedures to ensure a high standard of data quality and data completeness. Further, PAP usage can be reliably determined from PAP tracking systems.
OSA is an important and common lung disease, and studies that could improve the care of these patients are thus of significant relevance to the aims of the Lung Association. The results from this study will provide data for future studies to evaluate if improving air quality may improve OSA control on PAP and PAP treatment adherence. Our findings will inform policy and regulation decisions requiring an estimation of the total burden of morbidity due to air pollution. If positive, the results from this study linking air pollution with OSA will provide an additional mechanism for the association between air pollution with cardiovascular disease.
Dr. Ewan Goligher
Extracorporeal Life Support and Ventilator-Induced Diaphragm Dysfunction
Every year in Ontario, around 40,000 patients develop severe breathing difficulties and require life support from a breathing machine (mechanical ventilator). By pumping oxygen into the lungs and removing carbon dioxide from the lungs, the mechanical ventilator can save their life. However, the mechanical ventilator can also harm the patient by injuring the lung and/or the diaphragm (the main breathing muscle). Patients who develop diaphragm weakness experience a very delayed recovery because they become too weak to breathe on their own. This delay increases the chances of serious complications in the intensive care unit and increases the risk of long-term disability and death even after leaving the intensive care unit.
The purpose of this study is to determine whether a new form of respiratory support (using an artificial lung, also known as artificial lung support) can prevent diaphragm injury and weakness. Artificial lung support can avoid the need for mechanical ventilation and may therefore avoid diaphragm injury due to mechanical ventilation. The study is also designed to compare the changes in the diaphragm seen on ultrasound to signs of diaphragm injury seen under the microscope. Insights from this research will help to design new strategies for mechanical ventilation that prevent diaphragm injury and weakness.
We will enroll patients with respiratory failure undergoing respiratory support either by mechanical ventilation and/or artificial lung support while awaiting lung transplantation. We will obtain ultrasound measurements of the diaphragm before transplantation and then obtain small samples of diaphragm muscle tissue during the lung transplant surgery. After the surgery, we will continue to obtain ultrasound measurements of the diaphragm until the patient comes off the mechanical ventilator.
One of the key challenges to studying the diaphragm is obtaining samples of muscle tissue for study because the diaphragm is inside the body (between the chest and abdomen). To overcome this challenge, we will study patients undergoing respiratory support while awaiting lung transplantation. This approach will allow us for the first time ever to compare the changes in the diaphragm due to artificial lung support or mechanical ventilation and to confirm that ultrasound can help us to “see” what is happening to the diaphragm during respiratory support. If artificial lung support leads to less diaphragm injury and weakness compared to mechanical ventilation, this will substantially re-envision our approach to caring for patients with severe breathing difficulties around the world.
Severe breathing difficulties requiring ventilator support are common and carry a high risk of death. Patients who are able to survive their critical illness often have severe difficulty recovering and getting back to a normal life; many of them live with significant long-term disability. This study will inform the design of ventilation strategies that can prevent diaphragm injury and weakness during respiratory support. Preventing diaphragm injury may substantially reduce the burden of prolonged ventilation on the healthcare system and ameliorate the risk of death and long-term morbidity for patients. Our ultimate goal is to enable patients to recover faster and more easily after severe breathing difficulties so that they live longer and with greater quality of life.
Dr. Melanie Chin
Evaluating the Impact of Patient Activation on Clinical Outcomes in CF
Cystic fibrosis (CF) is a common genetic disease that results in a high burden of daily symptoms and patients often die at a young age. CF treatment plans require daily time-consuming therapy and frequent assessments by the medical team. As a result, the management of CF and its complications places significant demands on our health care system, and worsening disease is associated with high cost. The cost of worsening disease means that patient participation and engagement in their own health is important ensure that we are keeping patients as healthy as possible and minimizing healthcare costs.
Patient activation is a measure of how engaged patients are in caring for their health. It has been shown that in patients with chronic disease, higher patient activation is associated with healthy behaviors, improved health outcomes, and decreased healthcare use when compared with patients with lower patient activation. Patient activation can be measured using a questionnaire, but it has not yet been used in patients with CF in the clinical setting.
Our objectives are to examine the relationship between patient activation, health care use (e.g. emergency department visits), and disease knowledge in patients with cystic fibrosis. Secondly, we will explore which factors are associated with low and high patient activation scores.
This study will include 60 patients with cystic fibrosis at The Ottawa Hospital. They will be asked to complete the Shortened Patient Activation Measure and Cystic Fibrosis Disease Knowledge Questionnaires. Health care use and patient factors will be gathered from their electronic medical record. Associations between patient activation, disease knowledge and outcomes will be determined using statistical measures.
Patient activation has been explored in multiple chronic diseases, but there is almost no information on patient activation in CF. However, CF is a complex chronic disease where patient engagement is paramount given the demanding treatment plans prescribed. This project is the first step to measuring patient engagement in cystic fibrosis and understanding its association with health comes in this patient population.
By exploring the understanding of patient activation in patients with CF, we will help health care providers understand how patient activation is related to health outcomes in CF. Given how complex and costly it is to care for patients with CF, our team thinks that patient activation should be used to identify patients at high risk for increased healthcare use. In the long term, we think that interventions aimed at improving patient activation could have a significant impact on the course of health in patients with CF and healthcare costs. This project represents the first step towards reaching this goal.
Dr. Miranda Kirby
Quantitative Computed Tomography Imaging of Lung Disease
The number of people diagnosed with chronic lung disease in Canada is increasing. Together with the increased number of Canadians affected with lung disease will be an increase in the number of Canadians needing health care services. It is estimated that the number of people hospitalized due to lung disease will more than double in the next 15 years, and in the next 30 years will cost Ontario over $310 billion. More research is needed to find new ways to reduce the burden of lung disease.
We proposed using computed tomography (CT) imaging of the lung to allow us to “see” the disease. The objective of my research program is to develop new ways of extracting information from CT images, and show that this new information can improve our understanding of how the disease develops and progresses, how to identify the earliest disease changes, and how to measure the effects of treatment.
We will first study a large cohort of participants with CT images that have already been collected as part of the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. The CanCOLD study has enrolled participants with and without chronic obstructive pulmonary disease (COPD) – a disease that affects the small airways, vessels and tissue (i.e. emphysema) in the lung. Using the CT images from CanCOLD, we will develop new measurements that describe where the disease is located in the lung, how the different diseases are related to each other (e.g. emphysema and small airway disease) and how the disease changes over time. Using these new measurements, we will then study how these measurements can be used in other lung diseases. In patients that have received a lung transplant, we will investigate how CT imaging measurements can predict if rejection will occur. In patients with cystic fibrosis, we will acquire images before and after treatment and determine which CT imaging measurements can identify changes in lung structure. Finally, in young adults that smoke cannabis, we will determine if imaging measurements can identify any early changes in lung structure.
The unique and innovative part of our project will be the development of new CT imaging measurements that can be used to improve our understanding of lung disease.
This research program will develop novel medical imaging tools for quantifying lung disease in order to: 1) identify the earliest disease features in individuals at risk of developing lung disease to provide new therapeutic targets, and, 2) translate the image analysis tools developed to other patient populations (e.g. lung transplant recipients, cystic fibrosis, cannabis) at collaborating hospitals to enable better patient management and, ultimately, contribute to the mandate of the Ontario Ministry of Health and Long Term Care to constrain costs and preserve high standards of care in Ontario. Knowledge transfer through the implementation of the research deliverables will also be facilitated through collaboration with industry (VIDA Diagnostics, Inc.). Importantly, this research will raise Ontario’s profile as a leader in lung imaging in the global academic community.
Characterize Idiopathic Pulmonary Fibrosis using Respiratory Oscillometry
Conventional pulmonary function tests (PFT) with spirometry, diffusing capacity, lung volumes by body plethysmography requires patient cooperation, technical expertise and specialized equipment that are not readily available in many clinical settings. Spirometry alone is often used as a screening tool. However, forced expiratory in 1 sec (FEV1) and forced vital capacity do not readily distinguish obstructive and restrictive defects, and are primarily metrics of central airway function with FEV1 remaining normal until 75% of the small airways are obstructed
Respiratory oscillometry (Osc) measures total respiratory impedance (Z), composed of resistance (R) and reactance (X) allowing us to measure dynamic lung compliance. Unlike spirometry that requires a forced expiratory effort, Osc is conducted during tidal breathing and has been shown to be a sensitive tool to measure small airway function. Osc has been used primarily in obstructive lung diseases. Osc parameters of restrictive diseases are not well characterized. Idiopathic pulmonary fibrosis (IPF) is one of the most common diagnosed form of Interstitial Lung Disease (ILD). The degree of lung fibrosis is often correlated with reduction in lung compliance.
Our objective is to characterize Idiopathic Pulmonary Fibrosis using respiratory oscillometry.
Since September 2019, we have enrolled 36 participants with IPF and anticipate to enroll total of 100 participants by July 2020. PFTs including six-minute walk tests and quality of life questionnaire are completed as part of these IPF participants clinical assessments at the University Health Network ILD clinic.
Common Pediatric Ventilation Practices Across Canada
Currently, there is a huge gap in knowledge for pediatric mechanical ventilation (MV) management. Limited data exists on this topic as there are considerable ethical liabilities when performing clinical trials on children. Limited research suggests protocols reduce adverse events and improve clinical outcomes.
Inconsistent MV practices and the lack of data in children make it difficult to determine the best practice. Protocols are available but vary across centers with minimal compliance. Thus, reducing variations in MV techniques may improve safety, efficiency and clinical outcomes.
The European Society of Pediatric and Neonatal Intensive Care (ESPNIC) consisting of physicians, is the first group to establish consensus recommendations on many aspects of pediatric MV management. This could be the first step to substantiating common practices in pediatric MV. In Canada, respiratory therapists (RRT) have a large responsibility in MV management, so it would be of interest to see if they agree with ESPNIC.
The objectives of this project are to discuss the knowledge gap in pediatric mechanical ventilation management and to discuss Canadian respiratory therapists’ perspectives on the consensus guidelines by the European Society of Pediatric and Neonatal Intensive Care
An e-Delphi survey will gather opinions and consensus from RRT practicing at different pediatric critical centers across Canada. Participants will be recruited by advertisements, direct contact and snowball technique. The goal is to recruit a minimum of 15 participants, at least 1 participant from each of the pediatric hospitals across Canada. RedCap will be used to deliver and collect data.
This e-Delphi survey will consist of 3 Rounds. The research team will review and revise the ESPNIC recommendations for Round (R)1’s survey. Participants in R1 will provide feedback on the statements. R1 responses will guide construction of the survey for subsequent rounds. For R2 and R3, participants will rate their opinions using a 5-point Likert scale. Consensus is defined when statements reach >75% agreement or disagreement. Percentages, central tendency and standard deviations will be reported in and between rounds.
The audience will have the opportunity to anonymously participate by polling to provide feedback on this study. This will encourage discussions on ideas that may be incorporated into the e-Delphi and future studies.
RRT consensus on pediatric MV management will provide insight to common Canadian practices, in comparison to Europe. This will expedite the standardization of Canadian pediatric MV practices and facilitate future research to understand their clinical outcomes.