ABSTRACT
Non-invasive ventilation (NIV) is increasingly used in addition to exercise training in patients with chronic obstructive pulmonary disease with the purpose to allow them to train at higher intensities. Different modalities of assisted ventilation have been used with benefits for relief of dyspnoea and increase in exercise capacity. Nevertheless there are some potential problems with the use of NIV in pulmonary rehabilitation programmes. Despite promising results, a generalised use of NIV during exercise training programmes is unlikely to have a role in routine settings. The use of NIV during exercise training as a component of pulmonary rehabilitation should be reserved to individual cases.
Advanced chronic obstructive pulmonary disease (COPD) is a life-limiting condition associated to extreme breathlessness and peripheral muscle fatigue during exercise Citation(1). The expiratory flow limitation and increased respiratory rate observed in these patients during exercise may result in dynamic hyperinflation and tidal breathing at lung volumes close to the total lung capacity Citation(2). Dynamic hyperinflation is associated to an increase in the intrinsic positive end-expiratory pressure (PEEPi) and in the elastic work of breathing (WOB) Citation(3).
Exercise training is the core component of pulmonary rehabilitation programmes (PRPs). According to the most recent American Thoracic Society/European Respiratory Society statement, PRPs including aerobic exercise training have stronger evidence of effectiveness to improve exercise capacity, dyspnoea and health-related quality of life (HRQL) than almost all other therapies in COPD Citation(4). Although data are available in patients with low-to-moderate COPD Citation(5), current guidelines like the Global Initiative for Chronic Obstructive Lung Disease Citation(6) give few recommendations on modalities and effectiveness of training in more severe patients, with or without chronic respiratory failure. A recent meta-analysis shows that exercise training also improves exercise tolerance and HRQL in these very severe COPD patients Citation(7). Furthermore a recent study reported that the severity of airway flow limitation was not related to PRP outcomes and some very severe COPD patients can be considered as either “very good responders” or “poor responders” independent of the severity of airways obstruction Citation(8).
Recently, there has been an increasing use of non-invasive ventilation (NIV) during exercise training programmes with the purpose to train patients at intensity levels higher than those allowed by their pathophysiological conditions (Citation5, Citation9, Citation10). This progress as well as other tools Citation(11) might allow “personalised” sequential levels of intervention for PRP Citation(12). Although it is also used in other pathological conditions Citation(9), this review describes the use of NIV as a tool to increase the benefits of PRP in COPD patients.
We searched papers published between 1985 and 2017 in English in PubMed and Scopus databases using the keyword: “Non invasive ventilation AND exercise AND COPD” (152 papers, 51 reviews out of 152 papers), “Pulmonary rehabilitation” and “Exercise training.”
Rationale
It has been reported that muscle blood flow and metabolic demand are matched in COPD patients, indicating a minimal impact of heterogeneity on muscle oxygen availability at submaximal levels of exercise Citation(13). In these patients, assisted ventilation should provide symptomatic benefits, improving dyspnoea by unloading and assisting the overburdened and less effective inspiratory muscles with an inspiratory support Citation(14) and reducing WOB with an external PEEP or continuous positive airway pressure (CPAP) Citation(15). Some physiological studies support this hypothesis.
In healthy trained bikers, the WOB to face high-intensity exercise showed a significant and inverse correlation with blood flow to legs Citation(16). In conditions such as COPD during exercise, WOB increases with worsening dyspnoea, and blood flow may switch off from limbs to respiratory muscles, leading to earlier peripheral muscle fatigue – another reason for exercise interruption. This competition may be minimised by adding assisted ventilation during exercise. Assisted ventilation improved leg muscle oxygenation during exercise in COPD patients and prevented exercise-induced diaphragmatic fatigue (Citation17, Citation18).
Other issues may be relevant. Systemic inflammatory mediators are increased in response to exercise in these patients Citation(19). It has been suggested that in muscle-wasted COPD patients, assisted ventilation may prevent the interleukin-6 response to exercise Citation(20) as well as influence other endogenous factors in healthy people Citation(21). Furthermore, NIV may influence the vegetative activity observed in these COPD patients (Citation22, Citation23). summarises the potential mechanisms of NIV action during exercise.
Table 1. Potential mechanisms of NIV effect during exercise.
Physiological studies
CPAP and different modalities of assisted ventilation have been delivered by nasal, face masks or mouthpieces during exercise to patients with COPD Citation(24).
Continuous positive airway pressure
Although it is not a “real” mode of mechanical ventilation, from a theoretical standpoint, CPAP might reduce the dynamic hyperinflation-associated increased inspiratory threshold load on the inspiratory muscles of COPD patients and optimise neuromuscular coupling; thus, relieving breathlessness and increasing exercise tolerance (Citation15, Citation25), counterbalancing and, at least in part, the PEEPi Citation(26). To maximise benefits, the level of CPAP should be tailored to the individual patient: this involves the invasive measurement of PEEPi, a difficult, if not impossible, manoeuvre on a routine setting.
Inspiratory pressure support
With inspiratory pressure support (IPS) each breath may be triggered and supported by the patient or by the ventilator when a backup respiratory rate is set Citation(14). In severe COPD patients during exercise, inspiratory positive airway pressure (IPAP) relieves breathlessness and increases exercise tolerance by reducing the high WOB (Citation27–29). In a study Citation(28) IPS increased minute ventilation as a result of changes in both tidal volume and respiratory rate. This occurred despite marked reductions in inspiratory effort, as indicated by the pressure-time integrals of oesophageal and transdiaphragmatic pressures. Using a 5-point bidirectional scale to assess changes, breathlessness improved significantly with the addition of IPS and worsened to a similar degree when it was removed Citation(28).
Under IPS, these patients can sustain exercise-induced lactatemia longer than without ventilatory assistance Citation(30). Furthermore it has been found that during exercise non-invasive IPS with external PEEP resulted in additional benefit to hyperoxia in improving central haemodynamics and cerebral oxygenation in COPD patients with exercise-induced desaturations Citation(31).
Proportional assist ventilation
Proportional Assist Ventilation (PAV) provides inspiratory flow and pressure in proportion to patient's effort and timing Citation(32). Despite the promising characteristics, this modality is still not used routinely in Intensive Care Unit. Some studies show that non-invasive PAV can also increase exercise capacity of COPD patients without any relevant haemodynamic effect (Citation33–35).
Non-invasive ventilation in pulmonary rehabilitation programmes
The above physiologic studies suggest that, CPAP, IPS or PAV applied non-invasively during exercise, reduce WOB and breathlessness, thus increasing exercise tolerance. The following step is to assess NIV as a tool during PRP. In a study Citation(36), patients with stable COPD without hypercapnia, undergoing a 6-week multidisciplinary outpatient exercise training, were randomised to training during either mask PAV or spontaneous breathing. Assessment included exercise tolerance, dyspnoea, leg fatigue and HRQL. Twenty-eight % of the patients in the PAV group dropped out due to lack of compliance with the equipment. Both groups showed significant post-training improvements in exercise tolerance, breathlessness and leg fatigue, but not in HRQL, without any significant difference between groups. It was concluded that with the modality and in the patients assessed, assisted ventilation during a training programme was not well tolerated by all patients and gave no additional physiological benefit in comparison with exercise training alone.
Another study Citation(37) evaluated patients with more severe COPD undergoing a 6-week supervised outpatient exercise programme. Patients were randomised to exercise with PAV or to exercise unassisted. Before and after training, the patients performed a maximal symptom limited incremental cycle test. Minute ventilation, heart rate and arterialised venous plasma lactate concentration were measured before and after each test. Mean training intensity at 6 weeks was higher in the group under ventilatory assistance. Peak work rate after training was higher in the assisted group. Lactate, at an identical workload after training, was reduced by 30% in the assisted group and by 11% in the unassisted group. The authors concluded that PAV enables a higher intensity of training in patients with severe COPD, leading to greater improvements in maximum exercise capacity with evidence of true physiological adaptation Citation(37).
In a more recent study COPD patients were randomised into exercise training alone, NIV alone or both. Levels of interleukin 8 and tumour necrosis factor α decreased after NIV; interleukin 8, C-reactive protein and surfactant protein D decreased after training alone; whereas all inflammatory markers fell after the combined treatment Citation(38). Other investigators have confirmed the benefits of NIV during exercise training as a part of a PRP, also including the addition of heliox or inspiratory muscle training (Citation39–41).
Other applications
Addition of night NIV to day-time exercise training in severe stable COPD patients resulted in significant improvement in exercise capacity and HRQL compared with patients undergoing exercise training alone (Citation42–44). Furthermore, in COPD patients under long-term home ventilatory support NIV was also administered during walking, resulting in improved oxygenation, decreased dyspnoea and increased walking distance (Citation45, Citation46). Nevertheless the use of NIV during walking without the addition of supplemental oxygen does not prevent exercise-induced hypoxaemia in patients with stable hypercapnic COPD Citation(47). NIV may improve exercise tolerance in patients with acute respiratory diseases, but its applicability in clinical routine is limited (Citation48, Citation49). Recently, wearable devices have been introduced to be used during exercise Citation(50).
Problems
There are potential problems associated with using NIV in exercise training sessions () (Citation9, Citation10):
| 1. | Interfaces. During high-intensity exercise requiring high levels of ventilation, some patients may breathe (also) through their mouth, with increasing air leaks, therefore requiring a full-face mask or a mouthpiece. Full-face masks may be more uncomfortable than nasal masks, potentially reducing compliance to the procedure. | ||||
| 2. | Comorbidities. Most COPD patients have high prevalence of comorbidities including ischaemic cardiac disease. (Citation51, Citation52). The relief of exercise breathlessness associated to this “mechanical doping” Citation(53) might lead patients with unrecognised cardiac ischaemia to exercise at a load higher than their coronary ischaemic threshold. | ||||
| 3. | Practicalities. In the study Citation(36), due to lack of compliance, there was a high rate of drop-outs among patients exercising with NIV. Furthermore, the long time spent by an individual operator to apply mask, check for leaks, set and reset the ventilator to an individual patient may be other practical drawbacks. The increased patient to physiotherapist ratio increases the costs of the programmes. This is a particularly important cause of concern in an era of resource cuts, in the light of the well-known benefits of well-conducted standard PRP, not requiring complex and sophisticated machinery or a personalised physiotherapist Citation(4). | ||||
Table 2. Potential problems using NIV during exercise.
Open questions
Two recent meta-analyses were inconclusive (Citation54, Citation55). As application of NIV in PRP is a costly tool, we must identify the appropriate indications. Several questions remain open ():
| 1. | The ideal candidate. Differences in results of studies may be explained on the basis of different case mix. Further studies must identify the appropriate patient profile (e.g., level of obstruction; hypercapnic vs normocapnic; and naive vs acclimated to NIV and/or PRP). | ||||
| 2. | The most effective protocols. (e.g., training alone, vs nocturnal NIV and vs NIV under exercise). | ||||
| 3. | The most appropriate outcome measures. (e.g., tolerance to settings and equipment; incremental vs endurance test vs field tests; and HRQL vs dyspnoea vs daily life activities). | ||||
Table 3. Open questions for research using NIV during exercise.
Conclusions
There is a need for other randomised clinical trials with larger sample sizes based on statistical power calculations and designed to investigate the effect of training duration and intensity on rehabilitation. Despite promising results, for the above reasons and until the above questions are not answered, the authors of this review believe that a generalised use of NIV during exercise training programmes is unlikely to have a role in routine PRP settings. The use of NIV during exercise training as a component of pulmonary rehabilitation should be reserved to individual cases.
Declaration of interest
The authors declare that they have no actual or potential conflict of interest.
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