Background Patients with chronic obstructive lung disease (COPD) suffer from a progressive loss of lung function that leads to poor quality of life, and often invalidity and early death. This is markedly affected by a reduced exercise capacity and dyspnoea, but the underlying mechanisms are unknown. In the present study, we aim to investigate whether this may involve a reduced pulmonary blood volume secondarily to a reduced total blood volume.

Methods Design: Prospective matched comparative study Intervention: None

Outcomes:

The primary outcome is pulmonary blood volume estimated to total blood volume ratio between patients with COPD and healthy controls individually matched for age, sex, and height.

Statistical design:

All statistical analyses will be performed using R statistical software version 4.1.1 (R Project for Statistical Computing) within RStudio statistical software version 1.4.1717 (RStudio), and a two-tailed p<0.05 will be considered statistically significant. Inspection of normality and variance homogeneity will be done by creating qq-plots and histogram.

Regulatory considerations: This study will be submitted for approval by Regional Ethical Committee.

Perspective: This study will help uncover fundamental aspects of the pathophysiology of COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Pulmonary rehabilitation is a cornerstone in the management of COPD and it is considered the most effective non-pharmacological intervention for improving quality of life. However, its wider use is limited by an incomplete understanding of the mechanisms underlying exercise-induced improvements in COPD. Exercise training is generally thought to exert little effect on lung function, at least when assessed by dynamic spirometry or diffusion capacity measured at rest in the upright position. Rehabilitation is mainly considered a mean to alleviate symptoms, primarily by improving skeletal muscle function, but without the potential to reverse any structural changes within the pulmonary system, which are seen in patients with COPD. The rationale for recommending exercise as a way to reduce symptom burden and increase quality of life, is based on the finding from the most recent Cochrane review.

An early feature of COPD is pulmonary vascular dysfunction, characterized by loss of pulmonary capillaries driven by a disease-specific imbalance between angiogenic and angiostatic processes. Indeed, this is likely a mechanism that drives the progressive loss of lung tissue, and also limits exercise capacity as the ability to expand the alveolar-capillary membrane though pulmonary capillary recruitment and distension becomes limited, thereby critically attenuating oxygen uptake during exercise. These pulmonary vascular abnormalities lead to a reduction in pulmonary blood volume (PBV), a phenomenon particularly evident in the supine position, where blood is mobilised from the lower extremities and abdomen to the pulmonary circulation, thus recruiting and distending the available pulmonary capillaries. Using 82Rb-PET, we recently demonstrated that PBV is markedly reduced in patients with COPD. However, it remains to be established whether this reduction reflects pulmonary vascular dysfunction or is simply secondary to systemic hypovolaemia, as total blood volume (TBV) has not yet been characterized in this population.

In the present study, we therefore aim to compare TBV and PBV in patients with COPD to those of age-, sex, and height-matched healthy controls.

Objectives:

Primary objective: To investigate whether patients with COPD exhibit systemic hypovolaemia.

Secondary objectives: To investigate whether the COPD-associated reduction in PBV is caused by a reduced TBV and the extent to which this limits exercise capacity.

Research hypotheses:

Primary: Patients with COPD exhibit a lower PBV/TBV-ratio than healthy individuals.

Secondary: Patients with COPD exhibit both a lower pulmonary capillary blood volume (VC), PBV, and TBV, exercise capacity, and rest-to-exercise increase in pulmonary diffusing capacity than healthy individuals.

Inclusion Criteria:

• Inclusion criteria -patients

  • Men and women
  • 45-80 years
  • COPD (GOLD stage I to III)
  • Resting arterial oxygenation > 90% Inclusion criteria - controls
  • Men and women
  • 45-80 years
  • Normal FEV1, FVC, FEV1/FVC, and single-breath diffusion capacity
  • Same sex, age (± 3 years) and height (± 5 cm) as an included COPD patient
  • Low- to moderate activity level defined as < 1,5 hours of structured physical activity pr. week at moderate intensity and cycling < 30 minutes/5km pr. day at moderate intensity (moderate intensity = out of breath but able to speak)

Exclusion Criteria:

Exclusion criteria - patients

• Symptoms of ischaemic heart disease
• Known heart failure
• Previous severe or current COVID-19
• Claudication
• Symptoms of disease within 2 weeks prior to the study
• Participation in pulmonary rehabilitation within 6 months
• Known malignant disease
• Pregnancy
• Unstable cardiac arrhythmic disease
• Renal or liver dysfunction

Exclusion criteria - controls

• Known chronic lung disease
• Known ischaemic heart disease
• Known heart failure
• Previous severe or current COVID-19
• Symptoms of disease within 2 weeks prior to the study
• Known malignant disease
• Claudication
• Pregnancy
• Unstable cardiac arrhythmic disease
• Renal or liver dysfunction

Sjælland, Denmark