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 signals from muscles when exercising may be involved in chronic heart and lung conditions, and could also be present in PAH. They could contribute to breathlessness when exercising in PAH patients. The purpose of the present investigation is to better understand if, and why this happens. We are specifically investigating whether muscle sensors that respond to changes in stretch and chemicals formed during exercise are over-active in PAH, and overstimulate breathing in patients with PAH, leading to shortness of breath. It is hoped that our work will pave the way for future studies targeting these muscle sensors to reduce shortness of breath in PAH. This is a randomised crossover study involving participants with PAH and healthy controls. Participants will attend 2 study visits: Visit one: participants will complete health-related questionnaires, undergo spirometry, be familiarised with study procedures and complete a maximal handgrip trial Visit two: participants will complete two trials involving handgrip exercises. During one of the trials a blood pressure cuff will be inflated tightly over the right upper arm for two minutes. Breathing, blood pressure, heart rate and muscle-activation information will be recorded and participants will be asked about their level of exertion and breathlessness. Heart ultrasound (echocardiogram) will be performed to measure blood pressure in the pulmonary blood vessels.
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 one) tests the specific hypothesis that aberrant skeletal muscle afferent drives exertional dyspnoea and limits exercise capacity in patients with PAH.
Data
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 one) tests the specific hypothesis that aberrant skeletal muscle afferent 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 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, the investigator will explain the experiment process, participants will practice the handgrip manoeuvre, a blood pressure cuff will be inflated around the upper arm at 200mmHg for 1 minute). Maximal voluntary contraction (MVC) will be determined by instructing participants to perform 3 maximal handgrip efforts (squeezing a custom-made handgrip dynamometer with their dominant hand), separated by 1 minute. The highest will be taken as the MVC. 2. an experimental visit (about 2 hours). This will take place approximately 7 days following the familiarisation visit. Participants will be instrumented with equipment (noted below). Participants will perform two 8 minute handgrip trials. One will involve a normal recovery (control trial) and the other will involve post exercise circulatory occlusion (PECO) being induced in the exercising arm (PECO trial), thereby isolating the stimulation of skeletal muscle afferents after exercise. The test order will be randomised and separated by ~30 min. Participants will be supine on a laboratory couch rolled slightly toward a lateral decubitus position and hold a custom-made handgrip dynamometer with their dominant hand. Prior to the trials participants will rest for 15 minutes to establish steady-state ventilation variables and for baseline echocardiographic measurement of pulmonary artery systolic pressure (PASP) and cardiac output (CO). Both trials will consist of 2 minute baseline recording period then a 2 minute rhythmic isometric handgrip exercise task. During the handgrip exercise participants will be instructed to perform 1 second contraction of 50% MVC to 1 second of relaxation. Participants then either rest for 4 minutes (control trial) or a cuff will be rapidly inflated to 200mmHg around the upper right arm starting 2-3 contractions prior to the end of the exercise period. The cuff is deflated after 2 minutes and participants will rest for 2 minutes (PECO trial). Echocardiogram measurements of PASP and CO will take place during exercise, PECO/control and recovery. Ventilation will be measured continuously with a oro-nasal mask or mouthpiece (Hans Rudolph). Heart rate will be continuously measured using an electrocardiogram (3-lead). Blood pressure will be continuously measured with finger photoplethysmography. Oxygen saturation will be continuously measured with finger pulse oximeter. Diaphragmatic EMG will be measured using surface diaphragmatic electrodes attached to the skin. Echocardiography will be performed using a commercially available ultrasound machine with a cardiac transducer (1-3MHz). 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
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
• Patients with Group 1 PAH as per 6th World Symposium on Pulmonary Hypertension • Exertional dyspnoea (WHO functional class II and III) • Control participants free from PAH, age and sex-matched with no known health conditions • 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.
Outcome results
None listed