Non-Invasive Ventilation as an Adjunct to Exercise Training in Chronic Ventilatory Failure

Introduction

The term “respiratory failure” includes “pump failure” (ventilatory failure: manifested mainly as hypercapnia) and “lung failure” (gas exchange failure manifested mainly as hypoxaemia) [1]. Long-term home mechanical ventilation is increasingly used by patients with chronic ventilatory failure (CVF) due to advanced diseases such as chronic obstructive pulmonary disease (COPD), restrictive thoracic disease and neuromuscular diseases [2]. The last reported (and underestimated) prevalence of European patients requiring long-term assisted ventilation is 6.6 per 100,000 population [3]. Other surveys report prevalences ranging from 9.9 to 23 per 100,000 population [4^-6].

CVF may be associated with severe dyspnoea, limiting exercise capacity. Long-term non-invasive ventilation (NIV) may reduce patients’ symptoms, improve health-related quality of life (HRQL) and, in many cases, reduce mortality and hospitalisations [7^-9]. The effects on exercise capacity depend on the underlying diseases leading to CVF [10].

Pulmonary rehabilitation programmes including aerobic exercise training have stronger evidence of effectiveness in improving exercise capacity, dyspnoea and HRQL than almost all other therapies in patients with COPD, including those with very severe disease, and with a lower level of evidence in other pathologies [11^-13]. Therefore, current guidelines recommend pulmonary rehabilitation, including exercise training, in these patients [11^, 14]. Although there is some evidence of effectiveness of exercise training also in patients with CVF [15], there are few data in patients requiring long-term NIV.

Assisted ventilation is increasingly used during exercise training programmes in order to train patients at intensity levels higher than allowed by their clinical and pathophysiological conditions [16]. This, as well as other tools [17], may allow to widen the “personalised” sequential levels of pulmonary rehabilitation for the most severely affected patients [18]. This narrative review updates the possibilities of exercise training in patients with CVF and the use of NIV as a tool to increase the benefits of exercise in these patients.

Methods

We searched papers published (or with at least the summary) in English language between 1985 and 2018 in PubMed and Scopus databases using the keywords “chronic respiratory failure AND exercise,” “non invasive ventilation AND exercise,” “pulmonary rehabilitation” and “exercise training.”

Exercise Training for Patients with CVF

Well-designed randomised controlled trials (RCTs) of different length (from 2 months to 2 years) showed that adding night-time NIV to day-time exercise training in severe stable COPD patients resulted in significant improvement in exercise capacity and HRQL compared to patients undergoing exercise training alone [19^-21]. Two randomised cross-over trials on small populations of patients showed that walking with NIV resulted in improved oxygenation, decreased dyspnoea and increased walking distance in patients with COPD under home NIV [22^, 23]. However, another randomised cross-over physiological study on few patients showed that the use of NIV during walking without supplemental oxygen did not prevent exercise-induced hypoxaemia [24].

Exercise training has also been evaluated in a RCT in patients with kyphoscoliosis under NIV with beneficial effects on exercise capacity, muscle strength, dyspnoea and HRQL after 12 weeks [25]. In a RCT on a small sample size of patients with restrictive thoracic disease, home-based exercise training with NIV was effective and feasible [26], confirming an old physiological small study [27]. A non-randomised study showed that an individually tailored pulmonary rehabilitation programme plus night-time NIV was feasible in hypercapnic patients with interstitial lung disease and significantly improved exercise capacity and HRQL [28].

In a recent RCT on an adequate sample size of obese patients with obstructive apnoea syndrome treated with continuous positive airway pressure (CPAP), the addition of respiratory muscle training or NIV to exercise training did not result in any further improvement in functional capacity as compared to exercise training alone. However, the addition of NIV to exercise training was superior in improving cardiometabolic risk factors [29]. A single-centre pilot RCT showed that in patients with obesity hypoventilation syndrome, a 3-month rehabilitation programme, in addition to NIV, resulted in improved weight loss, exercise capacity and HRQL at the end of the rehabilitation period, but these effects were not maintained at 12 months [30].

A recent retrospective study has shown that pulmonary rehabilitation was feasible and resulted in improvements in exercise capacity and HRQL also in patients awaiting lung transplantation on nocturnal NIV. Furthermore, despite more severe disease, patients under NIV had a greater benefit from rehabilitation than patients without NIV [31].

Recently, wearable ventilators have been proposed for exercise [32^, 33]. A study examined the effect of NIV in environments with different temperatures and humidities during different activities [34]. Overall, NIV resulted in similar physiological and perceptual responses under all environmental conditions. Use of NIV increased heart rate during the most strenuous tasks, indicating that NIV may stress cardiovascular function during moderate-to-high intensity activities. Whether these observations can be applied also to patients with CVF is unknown.

Physiological Effects of NIV on Exercise

In patients with COPD, NIV during exercise unloads the dysfunctional inspiratory muscles with an inspiratory positive airway pressure (IPAP) [35] and reduces the work of breathing (WOB) with an expiratory positive airway pressure (EPAP) or with CPAP [36].

Muscle blood flow and metabolic demand are matched in patients with COPD at submaximal exercise [37]. However, when WOB increases with increasing exercise intensity, blood flow may switch from the limbs to the respiratory muscles, leading to earlier peripheral muscle fatigue. This condition may be improved by adding assisted ventilation during exercise [38^, 39].

Other mechanisms may work. Assisted ventilation may prevent the inflammatory response to exercise in patients with COPD and muscle wasting [40] and influence some endogenous factors in healthy people [41]. Furthermore, NIV may reduce the sympathetic activation during exercise with positive effects on the cardiovascular system as well as on muscle function [42^, 43]. Nevertheless, there are no physiological studies in patients with CVF under long-term NIV. Table 1 summarises the potential mechanisms of NIV action during exercise.

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Theoretically, in COPD patients, CPAP might reduce the dynamic hyperinflation, relieving dyspnoea and increasing exercise capacity [44]. However, for optimal benefits, the level of CPAP should be tailored to the individual patient measuring the “intrinsic” positive end-expiratory pressure, a difficult or impossible manoeuvre to perform on a routine setting [45].

With inspiratory pressure support, each breath may be triggered and supported by the patient or by the ventilator [35]. In severe COPD patients during exercise, an IPAP relieves dyspnoea and increases exercise tolerance, reducing the high WOB [46], and patients can longer sustain exercise-induced lactataemia [47]. Furthermore, a double-blind RCT has shown that during exercise non-invasive IPAP with an EPAP improved central haemodynamics and cerebral oxygenation in patients with COPD and exercise-induced desaturations [48].

Proportional assist ventilation (PAV) provides inspiratory flow and pressure in proportion to patients’ effort and timing [49]. Non-invasive PAV increases exercise capacity of COPD patients without any relevant haemodynamic effect [50^, 51].

NIV and Exercise Training Programmes

In a RCT [52], patients with stable COPD without respiratory failure (mean forced expiratory volume at 1 s [FEV₁]: 48% pred.; mean arterial carbon dioxide tension [PaCO₂]: 39.5 mm Hg) undergoing an outpatient exercise training programme were randomised to training with or without a PAV mask. Twenty-eight percent of patients in the PAV group dropped out due to lack of compliance with equipment or setting. Both groups showed significant improvements in exercise tolerance, dyspnoea and leg fatigue. Another similar RCT [53] evaluated patients with more severe COPD (mean FEV₁: 28% pred.; mean PaCO₂: 42.6 mm Hg) undergoing supervised outpatient exercise training. Patients were randomised to exercise with or without non-invasive PAV. Mean training intensity and peak work rate after training were higher and lactate at iso-workload after training was reduced more in the group under PAV [53]. Exercise training with NIV was associated with a reduction in inflammatory markers in patients with COPD [54]. Other RCTs have confirmed the benefits of NIV during exercise training [55^-57] and during exercise training with the addition of heliox or inspiratory muscle training [58^, 59].

These studies indicate that NIV-assisted exercise training may be indicated also for patients with COPD not requiring long-term assisted ventilation, with severe clinical and/or physiological conditions as assessed by the level of dyspnoea, airway obstruction or PaCO₂.

However, 2 recent meta-analyses were inconclusive on the effect of NIV in exercise training programmes in COPD [60^, 61]. A meta-analysis [60] including RCTs that compared NIV during exercise training versus exercise training alone or exercise training with sham NIV in patients with COPD concluded that the small number (6) of included studies with small numbers of participants, as well as the high risk of bias within some of the included studies, limited the ability to draw strong evidence-based conclusions. Another meta-analysis [61] found only 8 studies (7 RCTs) providing a proper description of a training schedule. Due to the small number of the available studies, the small sample sizes and the complete absence of power calculation, the authors required more RCTs with larger sample sizes based on statistical power calculations and designed to investigate the effect of training duration and intensity on rehabilitation. The ATS/ERS pulmonary rehabilitation statement [11] concluded that NIV during exercise training is “difficult and labor intensive” and may only be feasible in specialist units. The authors of the present review share the conclusions of those meta-analyses [60^, 61] and the ATS/ERS statement [11] and additionally suggest more studies with sham ventilation as a control.

A summary of relevant RCTs on the use of NIV during exercise training is shown in Table 2. Potential problems using NIV in exercise training sessions are shown in Table 3 [16].

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The use of NIV during exercise training may be difficult in naïve patients not familiar with ventilators, interfaces and ventilator settings. Recently, patients with CVF on home nocturnal NIV and long-term oxygen therapy for at least 6 months were studied [62]. Patients of the study group performed NIV during exercise training sessions with the same ventilator, mask (85.7% face mask, 14.3% nasal mask) and, at the start of exercise, ventilatory setting (mean IPAP: 17.4 cm H₂O; EPAP: 6.5 cm H₂O; inspiratory time: 1.2 s) as used at home. The control group performed exercise without NIV. The addition of NIV resulted in a significantly greater improvement in endurance time. The incremental exercise test and dyspnoea improved significantly in both groups. Only patients with NIV improved their respiratory muscle function and leg fatigue, whereas HRQL was significantly improved only in controls [62].

Some Technical Considerations

Studies in patients with CVF [23^, 53^, 62] used only relatively low levels of IPAP (15–17 cm H₂O) during exercise with NIV. The effectiveness of the proposed pressures as high as needed to reduce PaCO₂ in the long term [7] during exercise training in patients with CVF is still unknown. Long-term NIV with adequate pressure to improve gas exchange did not have an overall adverse effect on cardiac performance [63]. Nevertheless, confirming an earlier study [64] in patients with pre-existing heart failure, the application of very high inspiratory pressures might reduce cardiac output [63]. However, the cardiovascular effects of the intrathoracic pressures during exercise in patients with CVF and different cardiovascular functions are unknown. A study indicated that NIV with IPAP (16 cm H₂O) and EPAP (5 cm H₂O) may improve stroke volume and exercise tolerance in selected patients with advanced COPD [65]. However, impaired responses of stroke volume and cardiac output, associated with a lack of improvement in exercise capacity, were found in a sub-group of patients with severe hyperinflation at rest [65]. Therefore, a preliminary evaluation of lung and cardiac function should be performed prior to submission to exercise with NIV.

During high-intensity exercise requiring high ventilatory levels, many if not most of the 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 the compliance with the procedure. Figure 1 shows a patient exercising with a face mask.

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The use of a plateau exhalation valve when NIV is added to exercise in patients with severe COPD must be considered. During exercise, with the increase in exhalation flow and respiratory rate, a reduced ability of a plateau exhalation valve to exhale gases out of the circuit may result in CO₂ rebreathing in patients ventilated by a single-limb circuit. This problem was evaluated by a study in patients with stable severe COPD performing a maximal symptom-limited cycle exercise test while ventilated on pressure support [66]. As compared to rest, during exercise there was a significant increase in mean expiratory flow and fractional concentration of end-tidal CO₂ and a significant decrease in mean expiratory flow of plateau exhalation valve; the tidal fractional concentration of inspired CO₂ significantly increased at peak exercise [66]. Therefore, a double-limb circuit might be necessary.

Most patients with CVF have a high prevalence of comorbidities, among which ischaemic cardiac disease is frequent [67]. The relief of exercise-induced dyspnoea associated with this “mechanical doping” [68] might lead patients with unknown cardiac ischaemia to exercise at an intensity higher than their coronary ischaemic threshold. A careful clinical and physiological assessment of the patient is required before submission to this modality of training.

In a study by Bianchi et al. [52], there was a high rate of dropouts among patients exercising with NIV. The long time required by the operators to apply interfaces, to check for leaks and to tailor the ventilator setting to the individual patient may be other practical drawbacks. The need of a greater physiotherapist-to-patient ratio increases the costs, whereas well-conducted standard pulmonary rehabilitation programmes are effective and do not require complex and sophisticated machinery or a personalised physiotherapist [11].

An additional issue is the evaluation and reduction of potential risks of exercise under NIV or even invasive assisted ventilation in ventilator-dependent patients in locations far from healthcare institutions. Tele-monitoring may be useful. Tele-monitoring is increasingly proposed for ventilator-dependent patients [69]. With tele-rehabilitation programmes, patients may perform exercises at home under supervision by a physiotherapist who may prescribe and change strategies and settings at distance [70]. Tele-rehabilitation might offer a valid aid in monitoring also patients performing exercise under NIV, but at present, there is no evidence yet.

Several questions remain open (Table 4): future research should evaluate (1) the ideal candidate; (2) the most effective protocols; (3) the most effective and least harmful setting; and (4) the most appropriate outcome measures.

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Potential Alternatives and Future Applications

The type of ventilatory mode may significantly affect exercise performance. Inefficient mechanical unloading and patient-ventilator asynchronies may limit the tolerance for exercise [71]. Proportional modes of assisted ventilation like PAV can translate into longer and more efficient training sessions [53]. A preliminary study [72] in intubated patients showed that proportional ventilation modes such as PAV and the more recently introduced Neurally Adjusted Ventilatory Assist (NAVA) [73] during exercise resulted in higher work efficiency and less increase in oxygen consumption compared to ventilation with inspiratory pressure support [72]. Whether these results can be translated to patients with CVF is unknown.

Alternative strategies other than NIV might be useful to improve exercise capacity in patients with CVF. High-flow nasal cannula (HFNC) can deliver up to 60 L/min of reheated, humidified air via nasal cannula, with or without additional oxygen. Above a flow of 20 L/min, HFNC generates a positive pressure in the upper airways [74], inducing an increase in alveolar ventilation, improvements in gas exchange and a reduction in WOB in patients with COPD [75^, 76]. Preliminary reports indicate that HFNC may improve exercise performance, oxygen saturation and perceived symptoms in patients with severe COPD and ventilatory limitation [77]. Whether these preliminary results can also be applied to patients with CVF should be the object of future research.

Tidal expiratory flow limitation (EFL_T) increases “intrinsic” positive end-expiratory pressure at rest and during exercise. The Forced Oscillatory Technique system can monitor EFL_T by measuring within-breath changes in reactance at 5 Hz [78]. Automatic adjustment of EPAP to minimize EFL_T during effort or training might allow to tailor EPAP, maintaining or improving blood gases, WOB and dyspnoea with better comfort.

Conclusions

There is a need for other and better-quality RCTs, compared with sham, to investigate the effect of optimal training duration and intensity of NIV-assisted exercise training in patients with CVF.

Disclosure Statement

The authors declare that there is no actual or potential conflict of interest.