Fig. 11.1
Oxygen time courses in pulmonary capillary when diffusion is normal and abnormal (e.g., because of thickening of the blood–gas barrier by disease) (Reprinted with permission of Wolters Kluwer Health/Lippincott Williams & Wilkins, West [2])
11.3 Symptoms and Complications of IPF
11.3.1 Dyspnea
Dyspnea is common in IPF and is a major contributor to impaired QOL and symptoms of depression [3–5]. The extent of dyspnea is closely related to pulmonary function, peripheral muscle weakness, and activities of daily living (ADL) score [6]. Exercise-induced hypoxemia contributes to dyspnea more in IPF than COPD: oxygen desaturation during the 6-min walk test (6MWT nadir SpO2) independently predicts dyspnea during the test and is reportedly more severe in patients with IPF than COPD [7]. As a result, patients are deterred from engaging in physical activity, need to take frequent rests, and take longer to recover after exertion. Managing dyspnea is therefore an important means of improving QOL in patients with IPF.
11.3.2 Exercise Intolerance
Reduced lung volumes and gas exchange abnormalities contribute to exercise intolerance as a result of dyspnea and leg fatigue in patients with IPF. Furthermore, decreased capillary blood volume and hypoxic pulmonary vasoconstriction may also contribute to exercise intolerance as a result of pulmonary hypertension and right heart failure.
In COPD, it has been shown that peripheral muscle dysfunction is also a factor determining exercise intolerance. Similarly, quadriceps force is reduced in patients with IPF and correlates with dyspnea at end-exercise and exercise capacity [8]. Although recent evidence-based guidelines for IPF did not recommend corticosteroid therapy, treatment with corticosteroid and/or immunosuppressants is nonetheless often used to manage refractory cough and rapidly progressive cases. Because steroid-induced myopathy has been reported to impair peripheral muscle function in these patients, corticosteroid therapy may in fact cause a further deterioration in exercise tolerance [9]. Many PR programs include peripheral muscle training, especially in the legs, with the aim of improving exercise tolerance.
11.3.3 Mood Disturbance and Depression
Idiopathic pulmonary fibrosis is a lifelong disorder that causes substantial morbidity and mortality. Dyspnea limits mobility and impairs the ability to engage in physical activity, and more than 40 % of patients with an above average dyspnea score have clinically meaningful symptoms of depression [10]. The prevalence of symptoms of depression in patients with interstitial lung disease (ILD) is higher than that in normal older subjects (23–27 % versus 9.8 %) [3, 10, 11]. Patients with IPF should be screened routinely for depression, and treatment of depression and management of dyspnea may need to be progressed in parallel to improve QOL.
11.4 Pulmonary Rehabilitation
The American Thoracic Society–European Respiratory Society consensus statement defines PR as a “comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies, which include, but are not limited to, exercise training, education, and behavior change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence of health-enhancing behaviors” [12]. Pulmonary rehabilitation is an established therapeutic intervention in COPD, improving exercise tolerance and QOL and reducing hospital admission. Although the mechanisms of respiratory limitation in IPF differ from COPD, similarities between the clinical consequences (dyspnea, exercise intolerance, fatigue, and depression) suggest that PR may also benefit patients with IPF.
Although evidence for the benefit of PR in IPF is limited compared with COPD, it has recently been reported that PR may result in meaningful short-term benefits in patients with ILD [12]. The recently revised American Thoracic Society–European Respiratory Society–Japanese Respiratory Society–Latin American Thoracic Association evidence-based guidelines for IPF recommend PR for the majority of patients (weak recommendation, low-quality evidence) [13]. Nevertheless, PR is becoming an increasingly important part of the non-pharmacological therapy of IPF.
11.4.1 Benefits of Pulmonary Rehabilitation on Exercise Capacity
Pulmonary rehabilitation programs generally comprise a 5–12-week outpatient program followed by home-based rehabilitation. The main component is exercise training that aims to improve strength and endurance. Endurance training can be achieved simply by walking, or a treadmill or stationary cycle ergometer can be used. Strength training regimens vary substantially between institutions, in terms of the exercise techniques, duration, and intensity.
There have been several reports that exercise tolerance evaluated by the 6-min walk test (6MWT) or endurance time was improved after 6–12-week PR programs [9, 14–20] (Table 11.1). A recent meta-analysis showed that the common effect for change in 6MWT distance was 35.63 m in favor of the PR group in patients with IPF [21], more than 28 m above the expected minimal important difference (MID) [22].
Table 11.1
Characteristics and outcomes of studies examining the role of pulmonary rehabilitation in idiopathic pulmonary fibrosis
Study | Study design | Sample size | Pulmonary function | Duration of PR, number of sessions | Outcomes |
|---|---|---|---|---|---|
Vainshelboim et al. [14] | RCT, PR versus control | n = 32 | FVC 66.1 ± 14.8 % pred | 12 weeks, 24 sessions | PR group |
DLCO 48.6 ± 17.2 % pred | 6MWT distance: 70.4 ± 77.0 m (+14.9 %)✝ | ||||
VO2 peak: 2.1 ± 2.3 ml/kg/min (+15.4 %)✝ | |||||
Anaerobic threshold: 2.4 ± 2.4 ml/kg/min✝ | |||||
mMRC: −0.73 ± 0.8✝ | |||||
SGRQ total score: −6.9 ± 6.5 points | |||||
Control group | |||||
6MWT distance:−10.6 ± 35.4 m | |||||
VO2 peak: −0.5 ± 2 ml/kg/min | |||||
Anaerobic threshold: −0.72 ± 1.8 ml/kg/min | |||||
mMRC: 0.35 ± 0.7 | |||||
SGRQ total score: 2.8 ± 3.6 points | |||||
Arizono et al. [15] | Prospective non-randomized, observational study: patients declining to participate were the control group | n = 53 | VC 70.8 ± 18.1 % pred | 10 weeks, 20 sessions | PR group |
DLCO 49.7 ± 15.9 % pred | 6MWT distance: 26.7 m (+6 %)** | ||||
Peak work rate: 5.9 W (+10 %)** | |||||
Anaerobic threshold: 105.7 ml/min (+22 %)** | |||||
Quadriceps force: 8.9 N (+10.7 %)** | |||||
Endurance time: 9.3 min (+163 %)** | |||||
Control group | |||||
6MWT distance: −20.6 m (−4.1 %) | |||||
Peak work rate: −3.5 W (−5.3 %) | |||||
Anaerobic threshold: −93.3 ml/min (−15.2 %) | |||||
Quadriceps force: 3.3 N (+4.0 %) | |||||
Endurance time: −1.1 min (−16.9 %) | |||||
Jackson et al. [16] | RCT, PR versus control | n = 21 | FVC 60 ± 11 % pred | 12 weeks, 24 sessions | PR group |
DLCO 44 ± 11 % pred | 6MWT distance: −6.2 m (−1.7 %) | ||||
Exercise time on cycle ergometer: 118 s (+64.1 %)* | |||||
Control group | |||||
6MWT distance: −15.3 m (−4.5 %) | |||||
Exercise time on cycle ergometer: 4 s (+2.8 %) | |||||
Holland et al. [17] | Prospective, non-randomized, controlled study: patients with non-IPF ILD as the control group | n = 25 IPF patients | FVC 76.4 ± 20.3 % pred | 8 weeks, 16 sessions | 6MWT distance: 21 ± 58 m (+5.7 %)* |
CRDQ dyspnea score: 2.7 ± 5.6 points (+17.6 %)* | |||||
DLCO 48.5 ± 19.1 % pred | |||||
Kozu et al. [18] | Prospective, non-randomized, uncontrolled study: no control group | n = 65 | FVC (% pred) | 8 weeks, 16 sessions | 6MWT distance |
MRC grade 2: 83 ± 11 | MRC grade 2: 31 m (+7 %)** | ||||
MRC grade 3: 67 ± 13 | MRC grade 3: 19 m (+5 %)* | ||||
MRC grade 4: 60 ± 16 | MRC grade 4: 9 m (+3 %) | ||||
MRC grade 5: 51 ± 11 | MRC grade 5: 0 m (−1 %) | ||||
DL CO (% pred) | Mental health score of SF-36 | ||||
MRC grade 2: 58 ± 20 | MRC grade 2: 6.9 points (+11.0 %)** | ||||
MRC grade 3: 35 ± 10 | MRC grade 3: 8.5 points (+19.8 %) | ||||
MRC grade 4: 28 ± 12 | MRC grade 4: 2.4 points (+5.7 %) | ||||
MRC grade 5: 21 ± 8 | MRC grade 5: −2.7 points (−7.7 %) | ||||
Kozu et al. [9] | RCT, PR in IPF versus MRC grade-matched COPD | n = 45 IPF patients | FVC 68.6 ± 16 % pred | 8 weeks, 16 sessions | 6MWT distance: 16.2 (7.1 to 25.4) m (+5.0 %)** |
DLCO 38.8 ± 20 % pred | Quadriceps force: 2.0 (0.9 to 3.1) kg (+9.8 %)** | ||||
ADL score: 1.1 (0.8 to 1.3) (+29.7 %)** | |||||
MRC grade: −0.4 (−0.6 to −0.3) (−13.3 %)** | |||||
Swigris et al. [19] | Prospective, non-randomized, controlled study: patients with COPD in previous study as control group | n = 21 IPF patients | FVC 73 ± 2 % pred | 6–8 weeks, 18 sessions | 6MWT distance: 61.6 ± 41.1 m (+22.3 %)* |
DLCO 38 ± 13 % pred | Fatigue severity scale: −1.5 ± 0.5 (−35.7 %)* | ||||
Nishiyama et al. [20] | RCT, PR versus control | n = 30 | FVC 66.1 ± 13.2 % pred | 10 weeks, 20 sessions | PR group |
6MWT distance: 42 m (+10.9 %)* | |||||
DLCO 59.4 ± 16.7 % pred | SGRQ total score: −2.9 points (−5.8 %)* | ||||
Control group | |||||
6MWT distance: −4 m (−0.8 %) | |||||
SGRQ total score: 3.1 points (+8.2 %) |
In IPF, exercise-induced hypoxemia is a major cause of exercise intolerance and limits improvements in strength and endurance during PR. Oxygen supplementation can lead to significant improvements in exercise capacity by increasing cardiac output and arterial oxygen content in chronic hypoxemic lung disease [23]. Hallstrand and colleagues reported that the timed walk test distance increased from 271.2 m to 345.6 m when oxygen was administered during the test in patients with IPF and resting peripheral oxygen saturation >88 % [24]. Although a recent guideline suggested that the quality of the evidence for the benefit of LTOT in IPF was very low, the benefit of oxygen supplementation during PR appears to be indisputable.
Exercise-induced hypoxemia may also contribute to metabolic acidosis in peripheral muscles. Pulmonary rehabilitation improves sustained submaximal exercise capacity and anaerobic threshold in patients with IPF, and it has been reported that PR reduces exercise-induced lactic acidosis and increases oxidative enzyme activity in peripheral muscles [15].
Quadriceps force, a predictor of exercise capacity, is also reduced in patients with IPF [8]. The training of peripheral muscles, especially in the lower extremities, as part of PR is reported to improve exercise tolerance significantly (by a mean of 10 %) [15], although substantially greater improvements are seen in COPD (23 %) [9]. Exercise training as part of PR is also reported to reduce heart rate at maximum iso workload, suggesting that a cardiovascular adaptation to training can be achieved [25], but it is not clear whether exercise training improves peak oxygen consumption in IPF [14, 25]. As exercise tolerance is limited by dyspnea and exercise-induced hypoxemia in many cases of IPF, exercise strength might not reach the peak oxygen consumption in moderate or severe cases.
Pulmonary rehabilitation in IPF appears to have beneficial effects on exercise tolerance immediately after the program, yielding improvements in muscle strength, the extent of exercise-induced lactic acidosis in peripheral muscle, and cardiovascular adaptation.
11.4.2 Benefits of Pulmonary Rehabilitation on Dyspnea
Dyspnea is common in IPF and one of the most disabling symptoms of the disease. Most of the research that has examined the influence of PR on dyspnea in IPF has been questionnaire based, using the Medical Research Council (MRC) dyspnea grade, Chronic Respiratory Disease Questionnaire (CRDQ), or Mahler’s transition dyspnea index.
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