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 increased nerve activity (i.e., sympathetic nervous system) and changes in the sensing of blood pressure in the pulmonary blood vessels 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 pressure respond differently in people who have PAH and lead to an over-active sympathetic nervous system. These sensors are located in lung blood vessels (known as pulmonary “baroreceptors”). It is hoped that our work will pave the way for future studies targeting these “baroreceptors” to reduce shortness of breath, and blood pressure in the lung. This is a non-randomised crossover study involving participants with PAH. Participants will attend 2 study visits: Visit one: participants will complete health-related questionnaires, undergo spirometry, be familiarised with study procedures and complete a 6 minute walk test Visit two: participants will have a very thin electrode inserted into their leg to measure nerve activity. They will undergo 2 trials. In the first trial, they will inhale nebulised normal saline (control), and a heart ultrasound (echocardiogram) will be performed to measure blood pressure in the pulmonary blood vessels. Breathing, blood pressure, heart rate, muscle nerve activity will be recorded. After a rest period, they will inhale nebulised iloprost, a medication used to reduce blood pressure in the pulmonary blood vessels. The same measurements, as in the first trial, will be performed after this.
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 two) tests the specific hypothesis that altered pulmonary baroreceptor responses drives excess sympathetic nervous system activation leading to exertional dys
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 two) tests the specific hypothesis that altered pulmonary baroreceptor responses drives excess sympathetic nervous system activation leading to exertional dyspnoea and limited 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 two visits to the study laboratory. 1. an initial familiarisation visit (~60 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 (all measuring instruments will be attached except for microneurography probes, and the investigator will explain the experiment process). Participants will perform an incremental cycle exercise test until exhaustion At one laboratory visit, the participant will be asked to lie in a semi-recumbent position on a bed and be instrumented for the measurement of heart rate, BP, ventilation, and sympathetic nerve activity recordings. The participant will then lie supine towards a slightly lateral decubitus position (to facilitate echocardiogram). During a rest period of 15 minutes, echocardiogram will be performed for baseline measurement of PASP and cardiac output (CO). A 5 minute resting period of recording sympathetic nerve activity, cardiovascular and breathing measures will be performed. Then the participant will be asked to do 5 minutes of slow deep breathing. The participant will inhale nebulised iloprost. Iloprost is a prostacyclin derivative and acts as a selective pulmonary vasodilator. It is routinely used in the treatment of PAH and CTEPH, and also in clinical practice during acute vasoreactivity testing.26 It has a favourable safety profile (as discussed later in section 5.1). Compared to inhaled nitric oxide (another pulmonary vasodilator), iloprost leads to greater reduction in pulmonary pressures in PAH,40 is simpler to administer, and is more routinely used in clinical settings. Participants will inhale iloprost, 5µg via nebuliser to vasodilate the pulmonary circulation. Measurement of heart rate, blood pressure, breathing and sympathetic nerve activity will be made. 10 minutes following completion of iloprost nebulisation, echocardiogram will be performed to assess PASP and CO. The participant will remain until 60 minutes post end of nebulisation of iloprost for monitoring. 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
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used) (Subject)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Patients with Group 1 PAH and Group 4 CTEPH 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, 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 • Allergy or intolerance to medications used in the study (iloprost) • Contra-indication to study medication (iloprost) • 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.
Outcome results
None listed