Understanding breathlessness in interstitial lung disease

It is known that peripheral chemoreceptors, lung afferents and skeletal muscle afferents all contribute to the regulation of breathing during physical exertion. Moreover, in chronic obstructive pulmonary disease (COPD), another common cause of exertion-related dyspnoea, there is emerging evidence that the sensitivity of these sensory afferent populations is dysregulated leading to exaggerated respiratory and cardiovascular responses. However, despite such sensory afferent pathways representing a potentially important therapeutic target for ameliorating exertional-dyspnoea in interstitial lung disease (ILD), their role in the control of breathing during exercise in ILD has not been studied. Therefore, our overarching hypothesis is that aberrant activation of chemoreceptors, lung receptor afferents and/or skeletal muscle afferents drives exertional-dyspnoea and limits exercise capacity in patients with fibrotic ILD. In order to test this hypothesis, three inter-related sub-studies will be conducted. This describes the intervention/exposure of sub-study three: Brief name: Effect of skeletal muscle afferents on dyspnoea and exercise capacity All sessions (familiarization and experimental visits) will be conducted at the Human Cardiorespiratory Physiology Laboratory, Level 7, Respiratory Physiology Department, Auckland City Hospital, Auckland District Health Board. Each visit will be conducted in a 'one-on-one' setting. 1) initial familiarization visit (~60min): the investigator will explain the nature of the procedures, answer any questions and obtain written informed consent form. Anthropometric (height, weight), demographic, thorough medical history and clinical assessment (Health screening Questionnaire, measurement of oxygen saturation) will be conducted. Questionnaires will be used to assess activity-related dyspnoea (Modified Medical Research Council Dyspnoea Scale) , health related quality of life (King’s Brief Interstitial Lung Disease Questionnaire) , and anxiety and depression (Hospital Anxiety and Depression Scale). Baseline spirometry will be performed according to established guidelines (participants will breathe in and out through a handheld spirometer for approximately 10 seconds while wearing a nose clip). 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 maneuver, a blood pressure cuff will be inflated around the upper arm at 200mmHg for 1 minute). 2) experimental visit (~60min): This will take place approximately 7 days following the familiarisation visit. Participants will be instrumented with equipment (noted below). Participants will perform two 8-min handgrip trials. One will involve a normal recovery (control trial) and the other will involve post exercise circulatory occlusion being induced in the exercising arm ("interventional" trial), isolating the stimulation of skeletal muscle afferents after exercise. The test order will be randomised and separated by ~30 min. Participants will be seated in an upright position and hold a custom-made handgrip dynamometer with their right hand. Prior to the trials participants will rest for 5 minutes in order to establish steady state ventilation variables. Maximal voluntary contraction (MVC) will be determined by instructing participants to perform 3 maximal handgrip efforts, separated by 1 minute. The highest will be taken as the MVC. The 'interventional' trial 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. At the end of the exercise task, 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. 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. Participants will be asked about their perceived level of exertion and breathlessness. The investigator (carrying out all trials) is a qualified medical doctor and holds a current Advanced Cardiac Life Support (ACLS) Level 7 certification. The investigator is experienced with all the procedures employed.