One to

two weeks before the study, participants visited the Pulmonary Research Room at Khon Kaen University to determine one repetition Birinapant solubility dmso maximum (1 RM) of both quadriceps muscles (Armstrong et al 2006) and familiarise themselves with the procedures. Participants were randomised to receive the experimental intervention (breathing with conical-PEP during exercise) and the control intervention (normal breathing during exercise) in the following order: either conical-PEP breathing followed by normal breathing and then vice versa or normal breathing followed by conical-PEP breathing and then vice versa (Figure 1). The recruiters were blinded to order of intervention because randomisation happened at a different site from recruitment. There was a washout period of at least 30 minutes between the four

interventions where participants rested so that heart rate, blood pressure, and inspiratory capacity returned to their initial pre-exercise level. Lung capacity, breathlessness and leg discomfort were measured pre and immediately post each intervention and cardiorespiratory function was measured pre and during the last 30 seconds of exercise by an assessor not blinded to the order of intervention. Statistical analysis was carried out by an investigator blinded to the order of intervention. Patients were included in the trial if they had moderate-to-severe chronic obstructive pulmonary disease GS-7340 chemical structure defined as forced expiratory volume in one second per forced vital capacity < 70%; forced expiratory volume in one second that was 30–79%

predicted and this reduction was not fully reversible after inhalation of a bronchodilator (Rabe et al 2007); were clinically stable and free of exacerbations for more than four weeks defined by change to pharmacological therapy, admission to hospital or emergency room, or unscheduled clinic visit; were independent of long term oxygen or domiciliary non-invasive positive pressure ventilation; and could communicate well. They were excluded if they had musculoskeletal impairments that limited leg mobility, cardiovascular disease, aminophylline neurological or psychiatric illness, or any other co-morbidities which would interfere with exercise. Medications were not changed and patients were administered a long lasting bronchodilator two hours prior to the start of the protocol to reduce static hyperinflation. The experimental intervention was conical-PEP breathing during exercise. Leg extension exercise at a load 30% of 1 RM with weights firmly strapped to the ankles, was carried out with the participants in sitting. Both legs were exercised, alternately, with approximately 15 contractions per leg per minute, while breathing through the mouthpiece fitted with conical-PEP (Figure 2). The conical-PEP device has a fixed orifice resistor consisting of a small conical plastic tube 4 cm in length and 2.5 cm and 0.