Pulmonary rehabilitation (PR) is a non-pharmacological intervention addressed to chronic obstructive pulmonary disease (COPD) and non-COPD chronic respiratory patients, a key management strategy scientifically demonstrated to improve exercise capacity, dyspnoea, health status and psychological wellbeing. The main body of literature comes from COPD patients, as they provide the core evidence for PR programmes. PR is recommended even to severe patients having chronic respiratory failure; their significant psychological impairment and potential for greater instability during the PR programme will be carefully considered by the multidisciplinary team. Optimizing medical management (e g, inhaled bronchodilators, oxygen therapy, non- invasive ventilation) may enhance the results of exercise training. Patients who already receive long-term domiciliary non- invasive ventilation (NIV) for chronic respiratory failure might exercise with NIV during exercise training if acceptable and tolerable to the patient. It is not advisable to offer long-term domiciliary NIV with the only aim to improve outcomes during PR course. There are different attempts to use both negative and positive NIV in limited clinical studies. Long-term adherence to exercise is an important goal of PR programmes and teams, targeting to translate all-domain gains of PR into increased physical activity and participation to real life. Being a reliable alternative for the future, studies should focus on pressure regimens, type of devices, acceptability and portability for everyday activities.

AECOPD – acute exacerbation of chronic obstructive pulmonary disease

BiPAP – bilevel positive airway pressure 
COPD – chronic obstructive pulmonary disease
CPAP – continuous positive airway pressure
CHRF – chronic hypercapnic respiratory failure
EPAP - expiratory positive airway pressure
FEV1 – forced expiratory volume in 1 second
GOLD – The Global Initiative for Chronic Obstructive Lung Disease
HOT-HMV – home oxygen therapy and home mechanical ventilation
HMV – home mechanical ventilation
HRQoL – health-related quality of life
ICU – intensive care unit
LTOT – long-term oxygen therapy
MIE – mechanical insufflation-exsufflation
6MWT – six-minute walking test
NIV – non-invasive ventilation
NPPV – non-invasive positive pressure ventilation
NPV – negative pressure ventilation
PaCO2 – arterial partial pressure of carbon dioxide
PAP – positive airway pressure
PAV – proportional assist ventilation
pNIV – portable non-invasive ventilation
PR – pulmonary rehabilitation
SpO2% - saturation of arterial blood with oxygen measured by pulse oximetry

The concept of pulmonary rehabilitation briefly

Pulmonary rehabilitation is described as a “comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, and behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease, and to promote the long-term adherence to health-enhancing behaviours” [1]. The main goal for PR programmes is to enhance physical activity towards normal levels, to return the patient to the highest possible capacity in order to achieve the maximum level of independence and functioning in the community [2, 3]. Despite being a cost-beneficial intervention, only approximately two-fifth of chronic respiratory patients have been informed by their health care provider about PR and its positive results. This might be an explanation why < 2>

COPD is a leading cause of morbidity and mortality, with an increased burden of disease worldwide and constitutes a major healthcare concern [5, 6]. COPD patients are referred to PR due to persistent respiratory symptoms and/or limited activities of daily living and an unsatisfactory response to medical treatment offered in primary care [7]. PR addresses breathlessness, the perceived discomfort of breathing, a common symptom to many respiratory and systemic diseases [8]. Breathlessness is the consequence of imbalance between the increased respiratory muscle load and reduced ventilatory capacity [8]. Neural respiratory drive, the electrical output from the brainstem to the respiratory muscles, increases in response to this imbalance and acts to maintain an appropriate ventilation, thus becoming a major contributor to the subjective breathlessness [8, 9]. Breathlessness occurs in COPD, with disease advancement or in AECOPD as a result of imbalance in the load-capacity- drive relationship of the ventilatory system [8], with dynamic hyperinflation and impaired gas exchange that worsen ventilation- perfusion mismatch [10]. 

COPD is known to induce, apart from respiratory symptoms, a decrease in muscle strength and endurance due to systemic inflammation, vulnerability to fatigue and a decline in exercise capacity and cardiac function [9, 11, 12, and 13]. A decrease in physical activity and the consecutive sedentary life, along to the weakened pulmonary function, will result in a vicious cycle with decline in health-related quality of life (HRQoL) and physical ability at a disproportionate rate comparing to the decline of lung function [11]. Therefore, COPD has extensively been reported as a complex disease affecting patients’ health beyond the lungs with multiple intrapulmonary and extra pulmonary components and considerable variability between individuals [2].

Multidisciplinary PR is a key component in the management of COPD [5], and has proved to be beneficial in patients with COPD in terms of improving exercise capacity, symptoms (as breathlessness, fatigue, and mood) and HRQoL [14, 15]; it reduces health care utilization, being one of the most cost-effective therapeutic strategies [5, 12]. PR is addressed to stable patients especially with moderate-to-severe disease, after an acute exacerbation, in intensive care unit, in perioperative period after a lung transplantation, before and after lung cancer surgery, and before endobronchial lung volume reduction [12]. It can be offered in a hospital- based outpatient setting, in an inpatient setting, a community-based setting and at the patient’s home [4].

Large differences in results may arise from exercise type, level of supervision, education and physiotherapy strategies, psychological support, use of medication and mostly of duration and frequency of the maintenance programmes [14]. The longer the duration of the PR programmes the greater sustained benefits in comparison with the shorter ones [14]. A contribution may have the patients’ adherence to the programme, severity of disease, comorbidities, and accessibility of the PR premises [14]. These benefits tend to wane over time and most measures of improvement return to baseline by 12-24 months [5, 14]. Therefore, experts recommend continuation of exercise training beyond initial PR in order to prevent a decline in exercise capacity [14]. Maintenance programmes may consist in simple techniques used in ambulatory, community, or home programmes [14]. Home-based exercise interventions are safe and beneficial, helpful for patients who lack access to or are unable to participate in centre-based PR programmes; the increase on PA derives from factors around the patients, like an active spouse, walking the dog and other pets, and grand parenting [16].

Exercise training is the cornerstone in PR programmes and the best approach for increasing muscle strength, decreasing symptoms, reducing mood abnormalities, improving cardiovascular function and the motivation for physical activity [12]. The target training intensity in the PR exercise setting is critically dependent on baseline exercise testing, which is associated with a learning effect [16]. The main components of exercise training programmes are endurance and resistance training that should be supervised at least twice weekly, more than 60% to 80% of the maximal work rate, delivered as high-intensity and dynamic, interval and continuous training [9, 12, 13, 17]; in parallel with these supervised sessions, there are recommended five unsupervised sessions of 30 min of PA per week, in line with standard healthy living advice [17]. Typical modes of aerobic exercise are walking or cycling [13]. In stable COPD patients, a combination of endurance and resistance training should be performed to maximize improvement in limb muscle function and whole- body exercise capacity [9].

Non-invasive ventilation or why to think about it

In advanced stages of respiratory disease, patients frequently develop chronic hypercapnic respiratory failure (CHRF). NIV is the standard treatment for patients with CHRF due to COPD and restrictive lung diseases, and a major indication for home mechanical ventilation (HMV) in Europe [6]. COPD patients benefit from NIV once they have COPD GOLD stage III or IV and CHRF (PaCO2 > 6.0 kPa) in a stable clinical condition. Recent pulmonary rehabilitation BTS guidelines [17] suggest that NIV during exercise training should be offered to patients who already receive domiciliary NIV. With increased use of high-pressure NIV for home therapy, the use of NIV during PR would become more feasible.

In patients with chronic hypercapnic respiratory failure, long-term non- invasive positive pressure ventilation (NPPV) improves important physiological variables such as blood gases and lung hyperinflation. Results from clinical studies have shown that NPPV improves exercise capacity, exercise-related dyspnoea, pulmonary cachexia, sleep quality and QRQoL. Moreover, NPPV treatment might be associated with fewer hospital admission and lower overall treatment costs [18]. The best results with long-term NPPV have been noticed in studies using more intensive forms of NPPV, with higher inspiratory pressures and high back-up frequencies that have improved or even normalised hypercapnia [6, 18, 19, and 20].

Köhnlein et al have conducted a study in 2014 with the intention to assess survival in chronic hypercapnic COPD patients using NPPV in addition to standard treatment for at least 6 hours at night and anytime during daytime. The results provided evidence that NPPV addition in a group of stable COPD patients reduces hypercapnia, improves overall survival, exercise capacity and HRQoL over 1 year when comparing with guideline-oriented COPD treatment without NPPV [18]. In the study conducted by Raveling et al in 2018, NIV was initiated in COPD patients in a stable condition and after an episode of acute respiratory failure using BiPAP ventilators [6]. Compliance to the ventilator after 3 months was

6.6 ± 2.0 hours per night and 80% of the patients have used NIV for more than 5 hours per night. A higher body mass index and forced expiratory volume in one second, a lower bicarbonate before NIV initiation, younger age and NIV initiated in stable conditions were independently associated with better survival [6].

In high-pressures, NIV may develop a haemodynamic compromise due to reduced venous return from high intra-thoracic pressures. These factors may affect results of NIV in NIV-naïve patients or in those with compromised cardiac performance [19]. Still, as shown by Dreher et al, high intensity NPPV using a controlled mode of ventilation with a mean inspiratory pressure of 29 mBar is well tolerated by COPD patients with hypercapnic respiratory failure. Hence, high-intensity NPPV is superior to low-intensity NPPV using an inspiratory pressure of 15 mBAR in controlling nocturnal hypoventilation in this population of patients [21]. It is also advantageous in improving dyspnoea during physical activity, lung function and HRQoL [21]. They have been reported two disadvantages of high-intensity NPPV: patients need more days in hospital to acclimatise and there is an increased expiratory leakage comparing to low-intensity NPPV [21].

Types of non-invasive ventilators

Negative airway pressure devices

Techniques to deliver ventilatory support have developed in 19th century and became popular during the polio epidemic in early 20th century [8]. There are two types of negative pressure ventilation (NPV). One is tank ventilation that provides intermittent sub-atmospheric pressure around the whole body. The other one is cuirass ventilator that provides negative pressure only around the chest and creates a gradient pressure between thorax and lower body, which may increase intrathoracic venous return, right cardiac output and lung perfusion [22]. Breathing pattern undergoing cuirass ventilator is a real approximation of the normal physiological breathing, with more natural distribution of air in the lungs. Hence, NPV does not restrict the patients’ activities and they can be more comfortable [22].

Positive airway pressure devices

Positive airway pressure (PAP) devices offer today a consistent solution; they unload respiratory system and increase its capacity, with a consecutive reduction in neural respiratory drive and breathlessness [8]. Limitation of negative pressure devices promoted development of PAP devices to deliver continuous positive airway pressure (CPAP) and bi- level pressure support. CPAP delivers a fixed level of positive airway pressure during the whole respiratory cycle [8].

Bi-level pressure support, known as NIV, delivers a positive pressure during expiration and a higher positive pressure during inspiration to support inspiratory effort. PAP devices deliver respiratory support through oronasal or nasal mask interfaces, and not through endotracheal tube or tracheostomy, thus being considered as non-invasive devices [8]. PAP devices have well established benefits in acute and chronic respiratory failure in a large range of conditions, including COPD, obstructive sleep apnoea, obesity-related respiratory failure, progressive neuromuscular disease (NMD) and cardiogenic pulmonary oedema, through restoring respiratory muscles load-capacity balance, promoting alveolar ventilation and improving gas exchange [8].

Non-invasive ventilation act as an adjunct to pulmonary rehabilitation

NIV may be used as an adjunctive therapy to PR that unloads the respiratory muscles with the aim to increase the intensity of exercise training in selected patients with severe chronic respiratory disease who have a suboptimal response to exercise [1]. The benefits appear to be more marked in patients with severe COPD, and higher tolerated positive pressure may lead to greater improvements [1], with improved exercise performance and reduced breathlessness [23]. COPD is characterized by recurrent exacerbations leading to episodes of severe clinical deterioration requiring hospitalization and ventilatory support. Persistent hypercapnia after an episode of AECOPD is associated with excess mortality and early hospitalization [24]. Non-invasive positive airway pressure (PAP) interventions, applied during exercise, at rest and in the end-of-life setting, can be used to restore the balance of respiratory muscle load and capacity, with reducing neural respiratory drive and dyspnoea [8].

Long-term oxygen therapy (LTOT) and non-invasive ventilation (NIV) are potentially valuable therapeutic options, especially in COPD patients with severe lung hyperinflation and exercise-induced desaturation noticed during exercise training as part of a comprehensive PR programme [16]. For patients with COPD and chronic hypoxia LTOT is crucial in terms of improving survival. In these cases, use of supplemental oxygen during exercise may be associated with reduced exertional SpO2 and increased exercise performance [25]. The addition of nasal positive pressure ventilation to LTOT in hypercapnic patients has been shown to improve arterial blood gases, dyspnoea, quality of life and survival [20, 23]. Oxygen saturation measured by pulse oximetry (SpO2) should be > 88% during exercise; if SpO2 is ≤ 88% while breathing room air, supplemental oxygen should be used to maintain SpO2 at > 88% [13, 26] or > 90

Pulmonary rehabilitation is described as a “comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, and behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease, and to promote the long-term adherence to health-enhancing behaviours” [1]. The main goal for PR programmes is to enhance physical activity towards normal levels, to return the patient to the highest possible capacity in order to achieve the maximum level of independence and functioning in the community [2, 3]. Despite being a cost-beneficial intervention, only approximately two-fifth of chronic respiratory patients have been informed by their health care provider about PR and its positive results. This might be an explanation why < 2>

COPD is a leading cause of morbidity and mortality, with an increased burden of disease worldwide and constitutes a major healthcare concern [5, 6]. COPD patients are referred to PR due to persistent respiratory symptoms and/or limited activities of daily living and an unsatisfactory response to medical treatment offered in primary care [7]. PR addresses breathlessness, the perceived discomfort of breathing, a common symptom too many respiratory and systemic diseases [8]. Breathlessness is the consequence of imbalance between the increased respiratory muscle load and reduced ventilatory capacity [8]. Neural respiratory drive, the electrical output from the brainstem to the respiratory muscles, increases in response to this imbalance and acts to maintain an appropriate ventilation, thus becoming a major contributor to the subjective breathlessness [8, 9]. Breathlessness occurs in COPD, with disease advancement or in AECOPD as a result of imbalance in the load-capacity-drive relationship of the ventilatory system [8], with dynamic hyperinflation and impaired gas exchange that worsen ventilation-perfusion mismatch [10]. 

COPD is known to induce, apart from respiratory symptoms, a decrease in muscle strength and endurance due to systemic inflammation, vulnerability to fatigue and a decline in exercise capacity and cardiac function [9, 11, 12, and 13]. A decrease in physical activity and the consecutive sedentary life, along to the weakened pulmonary function, will result in a vicious cycle with decline in health-related quality of life (HRQoL) and physical ability at a disproportionate rate comparing to the decline of lung function [11]. Therefore, COPD has extensively been reported as a complex disease affecting patients’ health beyond the lungs with multiple intrapulmonary and extra pulmonary components and considerable variability between individuals [2]. 

Multidisciplinary PR is a key component in the management of COPD [5], and has proved to be beneficial in patients with COPD in terms of improving exercise capacity, symptoms (as breathlessness, fatigue, and mood) and HRQoL [14, 15]; it reduces health care utilization, being one of the most cost-effective therapeutic strategies [5, 12]. PR is addressed to stable patients especially with moderate-to-severe disease, after an acute exacerbation, in intensive care unit, in perioperative period after a lung transplantation, before and after lung cancer surgery, and before endobronchial lung volume reduction [12]. It can be offered in a hospital-based outpatient setting, in an inpatient setting, a community-based setting and at the patient’s home [4]. 

Large differences in results may arise from exercise type, level of supervision, education and physiotherapy strategies, psychological support, use of medication and mostly of duration and frequency of the maintenance programmes [14]. The longer the duration of the PR programmes the greater sustained benefits in comparison with the shorter ones [14]. A contribution may have the patients’ adherence to the programme, severity of disease, comorbidities, and accessibility of the PR premises [14]. These benefits tend to wane over time and most measures of improvement return to baseline by 12-24 months [5, 14]. Therefore, experts recommend continuation of exercise training beyond initial PR in order to prevent a decline in exercise capacity [14]. Maintenance programmes may consist in simple techniques used in ambulatory, community, or home programmes [14]. Home-based exercise interventions are safe and beneficial, helpful for patients who lack access to or are unable to participate in centre-based PR programmes; the increase on PA derives from factors around the patients, like an active spouse, walking the dog and other pets, and grand parenting [16].

Exercise training is the cornerstone in PR programmes and the best approach for increasing muscle strength, decreasing symptoms, reducing mood abnormalities, improving cardiovascular function and the motivation for physical activity [12]. The target training intensity in the PR exercise setting is critically dependent on baseline exercise testing, which is associated with a learning effect [16]. The main components of exercise training programmes are endurance and resistance training that should be practised supervised at least twice weekly, more than 60% to 80% of the maximal work rate, delivered as high-intensity and dynamic, interval and continuous training [9, 12, 13, 17]; in parallel with these supervised sessions, there are recommended five unsupervised sessions of 30 min of PA per week, in line with standard healthy living advice [17]. Typical modes of aerobic exercise are walking or cycling [13]. In stable COPD patients, a combination of endurance and resistance training should be performed to maximize improvement in limb muscle function and whole-body exercise capacity [9]. 

Non-invasive ventilation or why to think about it

In advanced stages of respiratory disease, patients frequently develop chronic hypercapnic respiratory failure (CHRF). NIV is the standard treatment for patients with CHRF due to COPD and restrictive lung diseases, and a major indication for home mechanical ventilation (HMV) in Europe [6]. COPD patients benefit from NIV once they have COPD GOLD stage III or IV and CHRF (PaCO2 > 6.0 kPa) in a stable clinical condition. Recent pulmonary rehabilitation BTS guidelines [17] suggest that NIV during exercise training should be offered to patients who already receive domiciliary NIV. With increased use of high-pressure NIV for home therapy, the use of NIV during PR would become more feasible.

In patients with chronic hypercapnic respiratory failure, long-term non-invasive positive pressure ventilation (NPPV) improves important physiological variables such as blood gases and lung hyperinflation. Results from clinical studies have shown that NPPV improves exercise capacity, exercise-related dyspnoea, pulmonary cachexia, sleep quality and QRQoL. Moreover, NPPV treatment might be associated with fewer hospital admission and lower overall treatment costs [18]. The best results with long-term NPPV have been noticed in studies using more intensive forms of NPPV, with higher inspiratory pressures and high back-up frequencies that have improved or even normalised hypercapnia [6, 18, 19, and 20]. 

Köhnlein et al have conducted a study in 2014 with the intention to assess survival in chronic hypercapnic COPD patients using NPPV in addition to standard treatment for at least 6 hours at night and anytime during daytime. The results provided evidence that NPPV addition in a group of stable COPD patients reduces hypercapnia, improves overall survival, exercise capacity and HRQoL over 1 year when comparing with guideline-oriented COPD treatment without NPPV [18]. In the study conducted by Raveling et al in 2018, NIV was initiated in COPD patients in a stable condition and after an episode of acute respiratory failure using BiPAP ventilators [6]. Compliance to the ventilator after 3 months was 6.6 ± 2.0 hours per night and 80% of the patients have used NIV for more than 5 hours per night. A higher body mass index and forced expiratory volume in one second, a lower bicarbonate before NIV initiation, younger age and NIV initiated in stable conditions were independently associated with better survival [6]. 

In high-pressures, NIV may develop a haemodynamic compromise due to reduced venous return from high intra-thoracic pressures. These factors may affect results of NIV in NIV-naïve patients or in those with compromised cardiac performance [19]. Still, as shown by Dreher et al, high intensity NPPV using a controlled mode of ventilation with a mean inspiratory pressure of 29 mBar is well tolerated by COPD patients with hypercapnic respiratory failure. Hence, high-intensity NPPV is superior to low-intensity NPPV using an inspiratory pressure of 15 mBAR in controlling nocturnal hypoventilation in this population of patients [21]. It is also advantageous in improving dyspnoea during physical activity, lung function and HRQoL [21]. They have been reported two disadvantages of high-intensity NPPV: patients need more days in hospital to acclimatise and there is an increased expiratory leakage comparing to low-intensity NPPV [21]. 

Negative airway pressure devices

Techniques to deliver ventilatory support have developed in 19th century and became popular during the polio epidemic in early 20th century [8]. There are two types of negative pressure ventilation (NPV). One is tank ventilation that provides intermittent sub-atmospheric pressure around the whole body. The other one is cuirass ventilator that provides negative pressure around the chest only and creates a gradient pressure between thorax and lower body, which may increase intrathoracic venous return, right cardiac output and lung perfusion [22]. Breathing pattern undergoing cuirass ventilator is a real approximation of the normal physiological breathing, with more natural distribution of air in the lungs. Hence, NPV does not restrict the patients’ activities and they can be more comfortable [22]. 

Positive airway pressure devices

Positive airway pressure (PAP) devices offer today a consistent solution; they unload respiratory system and increase its capacity, with a consecutive reduction in neural respiratory drive and breathlessness [8]. Limitation of negative pressure devices promoted development of PAP devices to deliver continuous positive airway pressure (CPAP) and bi-level pressure support. CPAP delivers a fixed level of positive airway pressure during the whole respiratory cycle [8]. 

Bi-level pressure support, known as NIV, delivers a positive pressure during expiration and a higher positive pressure during inspiration to support inspiratory effort. PAP devices deliver respiratory support through oronasal or nasal mask interfaces, and not through endotracheal tube or tracheostomy, thus being considered as non-invasive devices [8]. PAP devices have well established benefits in acute and chronic respiratory failure in a large range of conditions, including COPD, obstructive sleep apnoea, obesity-related respiratory failure, progressive neuromuscular disease (NMD) and cardiogenic pulmonary oedema, through restoring respiratory muscles load-capacity balance, promoting alveolar ventilation and improving gas exchange [8]. 

Non-invasive ventilation act as an adjunct to pulmonary rehabilitation

NIV may be used as an adjunctive therapy to PR that unloads the respiratory muscles with the aim to increase the intensity of exercise training in selected patients with severe chronic respiratory disease who have a suboptimal response to exercise [1]. The benefits appear to be more marked in patients with severe COPD, and higher tolerated positive pressure may lead to greater improvements [1], with improved exercise performance and reduced breathlessness [23]. COPD is characterized by recurrent exacerbations leading to episodes of severe clinical deterioration requiring hospitalization and ventilatory support. Persistent hypercapnia after an episode of AECOPD is associated with excess mortality and early hospitalization [24]. Non-invasive positive airway pressure (PAP) interventions, applied during exercise, at rest and in the end-of-life setting, can be used to restore the balance of respiratory muscle load and capacity, with reducing neural respiratory drive and dyspnoea [8]. 

Long-term oxygen therapy (LTOT) and non-invasive ventilation (NIV) are potentially valuable therapeutic options, especially in COPD patients with severe lung hyperinflation and exercise-induced desaturation noticed during exercise training as part of a comprehensive PR programme [16]. For patients with COPD and chronic hypoxia LTOT is crucial in terms of improving survival. In these cases, use of supplemental oxygen during exercise may be associated with reduced exertional SpO2 and increased exercise performance [25]. The addition of nasal positive pressure ventilation to LTOT in hypercapnic patients has been shown to improve arterial blood gases, dyspnoea, quality of life and survival [20, 23]. Oxygen saturation measured by pulse oximetry (SpO2) should be > 88% during exercise; if SpO2 is ≤ 88% while breathing room air, supplemental oxygen should be used to maintain SpO2 at > 88% [13, 26] or > 90

Pulmonary rehabilitation is a unique non-pharmacological therapy addressed to symptomatic COPD and non-COPD patients with a poor HRQoL due to breathlessness and fatigue. Because of dyspnoea, patients become more socially isolated and finally housebound. PR, LTOT and NIV bring hope in this difficult and long-term fight with a chronic respiratory disease, encouraging patients to meet other people with same disability and fear from illness and death, to exercise together and to continue their lives in a better condition. There is enough room, need and available technology to implement NIV worldwide, to encourage both patients and researchers to look ahead and find the best answers for the reported practical problems.