None listed
Conditions
Brief summary
Pulmonary arterial hypertension (PAH) is a severe condition that causes progressive high blood pressure in the blood vessels of the lungs. Shortness of breath, particularly on exertion, is the most common symptom in PAH. It is distressing, limits patients’ ability to do activities, and reduces quality of life. Despite the current treatments for PAH, it is still a significant issue for patients. The reasons for breathlessness in PAH, and why PAH develops are not fully understood. New scientific evidence supports the idea that over-sensitive sensing of oxygen levels in the blood may be involved in PAH and dyspnoea. The purpose of the present investigation is to better understand if, and why this happens. We are specifically investigating whether specialised sensors in the body that respond to changes in blood oxygen become hyperactive in people who have PAH. These sensors are located in discrete regions of the body, namely in large arteries near the brain and are known as peripheral “chemoreceptors”. It is hoped that our work will pave the way for future studies targeting these “chemoreceptors” to reduce shortness of breath, and blood pressure in the lung. This is a single blinded randomised crossover study involving participants with PAH. Participants will attend 4 study visits Visit one: participants will complete health-related questionnaires, undergo spirometry, and be familiarised with study procedures. Participants will perform an exercise test on a stationary bike Visit two and three: an infusion through the veins of either dopamine (to block the "chemoreceptor") or 0.9% saline (control) will be given. Only one type of infusion will be given each visit, the order is randomly chosen. Participants will not be told which one they are receiving. The lung function test will be repeated. Participants will undergo a "hypoxic challenge test" where they breathe in a lower amount of oxygen than air. This is designed to test the sensitivity of the "chemoreceptor" and the effect of the dopamine on the "chemoreceptor". Participants will then do an exercise test on a stationary bike. Breathing, blood pressure and heart rate information will be recorded. Participants will be asked about their level of exertion and breathlessness.
Interventions
The central hypothesis of this study is that aberrant activation of skeletal muscle afferents, pulmonary baroreceptors and/or peripheral chemoreceptors drive exertional dyspnoea and limits exercise capacity in patients with pulmonary arterial hypertension (PAH). This is tested through 3 inter-related sub-studies.
This sub-study (sub-study three) tests the specific hypothesis that aberrant activation of the peripheral chemoreflex drives exertional dyspnoea and limits exercise capacity in patient
The central hypothesis of this study is that aberrant activation of skeletal muscle afferents, pulmonary baroreceptors and/or peripheral chemoreceptors drive exertional dyspnoea and limits exercise capacity in patients with pulmonary arterial hypertension (PAH). This is tested through 3 inter-related sub-studies. This sub-study (sub-study three) tests the specific hypothesis that aberrant activation of the peripheral chemoreflex drives exertional dyspnoea and limits exercise capacity in patients with PAH. Data will be collected in the Human Cardiorespiratory Physiology Laboratory, Department of Respiratory Physiology, Auckland City Hospital, Auckland District Health Board. Each study visit will occur in the presence of the chief investigator Dr Michael Plunkett, a qualified Respiratory Physician, and experienced in management of medical emergencies, having completed Advanced Cardiac Life Support (ACLS) certification, and having prior work experience in Intensive Care Medicine. This study will consist of three visits to the study laboratory. Each experimental visit will be separated by approximately 1 week. 1. an initial familiarisation and maximal cardiopulmonary exercise test visit (~90 min) where an investigator will explain the nature of the procedures, answer any questions and obtain written informed consent form (as described above). Once consent has been obtained, a review of the participant’s electronic medical records will be conducted and thorough medical history and clinical assessment (Health Screening Questionnaire attached) will be performed to assess inclusion/exclusion criteria. Provided the inclusion criteria are met and there are no exclusion criteria, the participant will be enrolled into the study. Anthropometric (height, weight) resting oxygen saturation measurements will be undertaken. Questionnaires will be used to assess activity-related dyspnoea (Modified Medical Research Council Dyspnoea Scale), health related quality of life (emPHasis-10), and anxiety and depression (Hospital Anxiety and Depression Scale). The participant’s most recent pulmonary function tests (spirometric volumes, static volumes and test of gas transfer) will be collected from the participant’s electronic medical records. Baseline spirometry will then performed (participants will breathe in and out through a handheld spirometer for approximately 10 seconds while wearing a nose clip), according to established guidelines. Participant will be familiarised with the study procedure. This consists of: -all measuring instruments will be attached to the participant -participant will undergo 2 minutes of isocapnic hypoxia (end tidal CO2 ~40mmHg and end tidal O2 of 45mmHg) -the investigator will explain the experiment process They will then perform a symptom-limited incremental cycle exercise test to determine peak workload, in accordance with international guidelines. 2. Experimental visit 2 and 3 (~1.5 hours each), participants will have either i.v. low-dose dopamine (2 mcg/kg/min) or control (intravenous saline) infused via a small 23 gauge peripheral intravenous catheter inserted either in the antecubital fossa or hand. The order of low-dose dopamine or saline infusion will be randomised, single blinded, and separated by approximately 7 days. After at least 10 minutes of infusion, transthoracic echocardiography will be assessed at baseline under each condition (low-dose dopamine and saline). Resting measurements will then be performed. Hypoxic challenge respiratory monitoring will be used to determine baseline peripheral chemoreflex sensitivity (control) and degree of peripheral chemoreflex block (with low-dose dopamine). This will involve breathing in a hypoxic gas mixture, aiming for end tidal CO2 ~40mmHg and end tidal O2 of 45mmHg. After a 10 minute recovery period, participants will then perform a constant work cycle exercise test (75% peak workload). Following the exercise the infusion will be stopped and intravenous catheter removed. During both the hypoxic challenge and cycle exercise test ventilation will be measured continuously with a oro-nasal mask or mouthpiece (Hans Rudolph). Heart rate will be continuously measured using an electrocardiogram (12-lead). Oxygen saturation will be continuously measured with finger pulse oximeter. During the exercise test blood pressure will be measured during the last 45s of each stage (each stage is 2 minutes) using an automated sphygmomanometer (SunTech). At the end of the exercise participants will be asked about their perceived level of exertion and breathlessness Adherence to the protocol and intervention will be ensured as each study visit takes place in the presence of, and is supervised by the chief investigator.
Sponsors
University of Auckland
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria • Patients with Group 1 PAH as per 6th World Symposium on Pulmonary Hypertension • Exertional dyspnoea (WHO functional class II and III) • Men and women • Aged 18 years or over
Exclusion criteria
• Group 2, 3, 4, 5 pulmonary hypertension • Six minute walk distance < 300m • Dyspnoea at rest (WHO functional class IV) • Significant left ventricular dysfunction (Left ventricular ejection fraction <40% or significant diastolic dysfunction) • Obstructive or restrictive lung disease o Pulmonary fibrosis or emphysema on chest radiograph or computed tomography scan o Total lung capacity <80% of predicted o Forced expiratory volume in first second of expiration/ forced vital capacity <70% o Currently taking regular inhaled therapy for airways disease • Serious co-morbidities that may contribute to dyspnoea and/or reduce exercise capacity including: o Severe cardiac disease (e.g., heart failure, coronary artery disease) o Severe respiratory disease other than PAH (e.g., chronic obstructive pulmonary disease, interstitial lung disease) o Severe obesity (Body mass index > 35 kg/m2) o Severe orthopaedic impairment or rheumatologic/ connective tissue disease o Significant neurological disease o Significant renal or liver disease o Infection or pyrexial illness o Uncontrolled thyroid disorders o Current active treatment for cancer • Presence of any contraindications to cardiopulmonary exercise testing o Unstable angina or recent acute myocardial infarction o Uncontrolled arrhythmias causing symptoms or haemodynamic compromise o Symptomatic severe aortic stenosis o Oxygen saturation <85% at rest on room air o Uncontrolled heart failure o Uncontrolled asthma o Uncontrolled thyroid disorders o Mental impairment leading to inability to cooperate o Long-term oxygen therapy • Current pregnancy • Current users of recreational drugs • Current abusers of alcohol • Inability to fully or appropriately provide consent (e.g., language issue, reading capability) • Underlying medical conditions, which in the opinion of the Investigator place the participant at unacceptably high risk for participating in the study. • Allergy or intolerance to dopamine • Contraindication to dopamine
Outcome results
None listed