Advances in Airway Clearance Technologies for Chronic Obstructive Pulmonary Disease

Christian R Osadnik; Christine F McDonald; Anne E Holland

Expert Rev Resp Med. 2013;7(6):673-685.

New Technologies & Approaches to Airway Clearance Therapy

Airway Clearance Devices

A large variety of airway clearance devices are commercially available, the two most recent being the Quake® and the Lung Flute®. The Quake is a pipe-shaped oscillatory PEP device that bears some resemblance to the more well-known Flutter®. A distinguishing feature of the Quake is the small handle that is manually rotated to generate oscillations. This is in contrast to most other PEP devices where oscillations are generated via expiratory effort. The Quake has been reported to generate greater mucus displacement than the Flutter or Acapella® devices in tracheal models,^[53] however there is little research in the COPD population and it is therefore difficult to define its role in clinical practice.

The Lung Flute is a small, self-powered audio device approved by the United States Food and Drug Administration in 2006 as adjunct therapy for sputum induction procedures. The theoretical merit underpinning its proposed physiological advantages over traditional back-flow pressure devices is yet to be clinically proven as is its role in the management of individuals with COPD.

Combining ACTs With Nebulization Therapy

Combining ACTs with nebulization therapy can be advantageous in reducing total treatment time for individuals with chronic respiratory conditions such as cystic fibrosis, who regularly use combinations of these. For example, combining a PEP device with nebulized medications means medication is inhaled on each inspiration while sputum clearance is promoted on each expiration. Reducing therapy time can be an important goal of therapy with the potential to increase treatment adherence and improve quality of life. It remains to be seen whether this occurs in individuals with COPD, particularly as the extent of sputum production is often less than in those with cystic fibrosis. There has been some interest in the effects of combining ACTs with inhaled aerosol medications such as bronchodilators in both AECOPD and chronic COPD.^[54–59] Most of these small studies compared the use of PEP devices such as the RC-Cornet®, Flutter or PEP mask, in combination with nebulized medication, to nebulized medication alone. Variable physiological responses were elicited on outcomes such as spirometric parameters, measures of lung resistance, reactance or conductance, or rates of aerosol particle deposition and/or clearance. Despite positive preliminary findings, however, there is little evidence to suggest that combinations of airway clearance and nebulized therapy have made a meaningful translation into the clinical environment in COPD. The merits of combining ACTs with nebulization therapy may therefore be an area worthy of future research.

The face of nebulization therapy has changed considerably over recent years due to advances in technology and improved product affordability. Jet nebulizers remain the mainstay of aerosol therapy delivery in COPD, particularly during AECOPDs. This is despite evidence suggesting at least equivalent outcomes via use of metered-dose inhalers with spacers.^[60–62] The range of newer nebulizers on offer means choice of medication delivery device, particularly for home use, may be influenced by factors such as nebulizer cost, portability, size, drug delivery time and ability to adapt with complementary therapies such as ACTs. While not the focus of this review, some of the benefits of newer nebulizers include:

The ability to deliver respiratory medications in smaller particle sizes (mass median diameter of particles <3–5 microns; e.g., Pari LC Sprint® Star);
More compact device sizes;
The use of vibrating mesh technology to increase drug total output rate and efficiency of drug delivery times (e.g., Pari E-flow® rapid; Aerogen Aeroneb®);
The incorporation of standard apertures into nebulizers to accommodate PEP-based airway clearance devices.

Exercise for Airway Clearance

The role of physical exercise as an ACT for individuals with COPD is not well defined. In theory, an increased depth and rate of breathing may contribute to the generation of airway shear forces, which may assist with sputum removal. Some support for this mechanism is provided by a study of exercise in adults with cystic fibrosis^[63] where significant improvements in ventilation, respiratory flow and ease of sputum expectoration were observed following 20 min of treadmill or cycle training. A significant reduction in sputum mechanical impedance occurred following treadmill training that was attributed to the physical effect of oscillatory trunk motion. However, people with cystic fibrosis are typically younger and have more sputum than people with COPD.

The only randomized trial to examine the effect of exercise on sputum clearance in a COPD cohort was conducted by Oldenburg and colleagues.^[64] The effect of 20 min of interval cycle ergometry was compared with postural drainage and coughing using scintigraphic measures of mucociliary clearance.^[64] The authors found small but significant (7.5%) improvements in mucociliary clearance following exercise, which were greater than those induced by postural drainage but significantly less than those achieved with coughing (40.8%).

There is strong evidence to support significant, clinically important benefits from participation in pulmonary rehabilitation (including physical exercise) during both the stable disease state^[65–68] and shortly after an AECOPD.^[69] These include reductions in hospital readmissions and improvements in quality of life and exercise tolerance. Supportive evidence is more limited regarding pulmonary rehabilitation during hospitalization for an AECOPD. Several studies have demonstrated that commencement of physical exercise programs during a hospital admission for AECOPD is safe and feasible.^[70–74] However, detailed guidelines regarding the ideal exercise intensity and duration for individuals with AECOPDs do not yet exist. This may pose a barrier to the more widespread use of exercise for airway clearance during periods of acutely increased respiratory symptoms. Tang and colleagues examined the appropriateness of a range of exercise training intensities during an AECOPD.^[71] They found that an exercise protocol comprising moderate–high intensity aerobic and resistance exercise was as well tolerated as a low intensity exercise protocol, without any increase in adverse events. Given the potential for significant benefits from this form of treatment, it appears important for the value of physical exercise during AECOPDs to be further explored, both as a modality of rehabilitation and as an ACT.

Non-invasive Ventilation for Airways Clearance

The use of non-invasive forms of ventilation such as bi-level positive airway pressure (BiPAP) or IPV for the specific purpose of airway clearance is not widespread in the management of individuals with COPD. The benefits of BiPAP as a first line form of therapy for the management of type II respiratory failure during an AECOPD are well recognized.^[75] By contrast, its effectiveness as an adjunct to sputum clearance in individuals with COPD has not been well studied. A unique feature of airway clearance methods using ventilatory support is the potential to enhance lung volumes and expiratory flow rates during circumstances where the respiratory system is significantly compromised, such as AECOPDs.

IPV is an airway clearance device that delivers high frequency bursts of oscillatory ventilatory support during both inspiration and expiration. It can be applied via a mouthpiece or mask and is used intermittently for the specific purpose of clearing sputum rather than as a mode of ventilation. There has been only one clinical trial investigating the effectiveness of IPV in COPD. In this randomized controlled trial of 33 patients with AECOPD and mild respiratory acidosis by Vargas and colleagues (2005),^[41] statistically significant short-term improvements in respiratory rate and arterial blood gas tensions of oxygen and carbon dioxide were found following a single 30-minute session of IPV with normal saline nebulization. After receiving IPV twice daily for an average of three days, participants in the treatment group also demonstrated a significantly shorter hospital length of stay and reduced need for ventilatory assistance over the course of the hospital admission than the control group who received usual care. The precise mechanism to explain these beneficial effects was not confirmed, however, a subsequent small physiological investigation (n = 10) by Nava and colleagues (2006)^[76] suggested IPV is capable of providing direct ventilatory support. It also demonstrated that IPV delivered at lower pulse frequencies (250 vs 350 percussions/min) was associated with reduced intrinsic positive end-expiratory pressure, an absence of hyperinflation or increase in expiratory muscle activation, and improved patient comfort. It is important to note this latter investigation was performed with individuals who had stable COPD and minimal sputum production. The physiological response to IPV may differ between acute and chronic disease states due to the significant changes that occur during an AECOPD. IPV could be a promising ACT for the management of individuals with AECOPD, particularly in terms of its potential to combine airway clearance with ventilatory support for individuals with respiratory compromise. The significant financial cost of a single IPV unit (in excess of 10,000 Euros), however, represents a considerable barrier to its more widespread use in clinical practice.

Novel Approaches to Determining the Effects of ACTs

A recent small investigation (n = 5) by Ides and colleagues appears to be the first known application of the forced oscillatory technique (FOT) for the evaluation of an ACT in individuals with COPD.^[77] FOT is a valid, non-invasive method of measuring lung impedance (the relationship between airflow and pressure) that can be performed without the need for specific breathing maneuvers.^[78] The technique involves measurement of the mechanical response of the lung to small amplitude soundwave driving signals or 'forced oscillations' that are passed through the airway opening (i.e., mouth) at distinct frequencies (typically 5–25 Hz). It has been used to characterize lung diseases such as asthma and COPD^[79–84] and to determine responsiveness to some inhalational therapies.^[85,86] The authors of this study did not observe any significant changes in lung resistance (derived from FOT or plethysmography), lung volume, respiratory muscle strength or oxyhaemoglobin saturation following a single session of IPV. The potential explanation for the lack of observed benefit is difficult to ascertain as important details regarding the study design were not reported.

A similar approach was reported by Figueiredo and colleagues (2010) in an investigation of the effects of the Flutter valve in individuals with bronchiectasis.^[87] In this study, impulse oscillometry was used to determine whether the intervention had any effect on airway resistance compared with a sham treatment (Flutter with steel ball removed). Impulse oscillometry is conceptually similar to FOT except the lung response to soundwaves is measured across all frequencies at once.^[88] The authors reported a significantly greater decrease in lung reactance and resistance (total and peripheral) following Flutter in association with significantly increased sputum wet-weight expectoration. The effects on respiratory mechanics were postulated to reflect improvements in ventilation heterogeneity, however, whether these physiological changes facilitated the sputum clearance or the sputum clearance caused the physiological changes remains unclear.

Multi-breath nitrogen washout (MBNW) is another technique capable of detecting subtle changes in small airways. This involves the analysis of alveolar gas concentrations across a series of breaths following a period of tidal breathing of 100% oxygen.^[89] Detailed data are generated regarding the extent of (abnormal) ventilation heterogeneity occurring in the convective (conductive) and diffusive-convective (acinar) regions of the lungs. Further details regarding the derivation of these parameters are described by Verbanck (2012).^[88] This technique was recently applied in a study seeking to investigate the mechanisms by which PEP mask therapy impacts sputum clearance in individuals with stable COPD and chronic sputum production.^[26] The authors found no significant differences in sputum expectoration, lung volumes or ventilation heterogeneity between a single session of PEP mask therapy compared with controlled huffing and coughing. The mechanism of action was therefore not able to be confirmed.

The use of imaging techniques for the purpose of evaluating the effectiveness of ACTs is not widespread. Most studies in this area relate to radio-aerosol tracer techniques (e.g., gamma ray imaging, scingitraphy) to measure mucociliary clearance.^[64,90–94] Such technology is reserved almost exclusively for the purpose of scientific research, not clinical patient management.

Ides and colleagues also examined the physiological responses to IPV using a novel computer tomography (CT) functional imaging technique in addition to FOT.^[77] In this industry-sponsored study, three-dimensional CT analyses were performed to enable visual evaluation of lung airway patency before and after treatment. The bronchial tree generation level to which these reconstructions related was not stated. An integrated computational fluid dynamic model enabled visual representation of the response to IPV for outcomes such as airway resistance via reconstructed three-dimensional lung images that were colored according to the magnitude of change per localized region of the bronchial tree. While no significant treatment effects were observed in this small investigation (n = 5), the authors concluded that the new imaging technique offered potential to identify effects of ACTs that were physiologically independent of changes in static lung volumes. As the application of such technology in evaluating ACTs is in its infancy, recommendations regarding its validity or potential role in future airway clearance investigations cannot be made until further evidence emerges.

It is possible that newer methods, such as this CT-derived model, may enhance the potential for such technology to translate into future clinical practice. This would depend largely upon the degree of accessibility and affordability of such technology in the clinical environment. Exploration of the effects of ACTs could also be justified using modern real-time imaging techniques such as hyperpolarized helium magnetic resonance imaging (MRI) or single photon emission computed tomography (SPECT). An example of a similar application was demonstrated in a recent case study of tracheomalacia.^[95] Using a 320-slice dynamic CT scanner, the authors were able to clearly demonstrate resolution of excessive dynamic airway collapse in the trachea following application of continuous positive airway pressure support. Before such technologies are applied for the purpose of determining response to ACTs, careful consideration must be given to the relative merits versus risks of radiation exposure inherent with some of these imaging procedures. The potential to identify the most physiologically appropriate technique for airway clearance using non-invasive technology in a clinical context is, however, a tantalizing prospect.

1 2 3 4 5 6 7 8 9 10 11 12

Next Section

Abstract and Introduction
What Are Airway Clearance Techniques?
Physiological Basis of Airway Clearance Techniques
Positive Expiratory Pressure in COPD
Systematic Reviews of ACT Effectiveness
Considerations in the Evidence
Recent Landmark Clinical Trials of ACTs During AECOPD
Clinical Practice Guidelines
The Use of Airway Clearance Techniques in Clinical Practice
New Technologies & Approaches to Airway Clearance Therapy
Expert Commentary
Five-year View
References
Sidebar

Table 1. Detailed overview of commonly used airway clearance techniques.
Type of ACT	Specific techniques	Rationale for use as an ACT
FET or huff	FET; huff	The FET involves carefully exhaling with the mouth and glottis open to generate mild dynamic airway compression and shift sputum into the large airways where it may be expelled by coughing. It can be performed from different starting lung volumes (i.e., after taking small – large inspirations) and may comprise expirations of different length (i.e., short–long expirations) and strength (i.e., gentle–strong expiratory force). These factors are altered according to the suspected location of sputum within the bronchial tree. The expiratory maneuver on its own is commonly referred to as a huff, whereas the FET describes cycles of huffing interspersed with periods of relaxed breathing. Huffs (and sometimes the FET) are frequently incorporated into other types of ACTs (e.g., the active cycle of breathing technique, positive expiratory pressure therapy).
'Conventional' therapy	GAPD MPD; Percussions & vibrations	GAPD: Specific positions (or postures) are used to orient regions (lobes or bronchopulmonary segments) of the lungs affected with sputum into positions whereby gravity can facilitate drainage 'downwards' toward the central airways. GAPD may be performed with a head-down tilt (lying postures involving the thorax being lower than the hips). MPD: Same as for GAPD except positions involving head-down tilts are modified to maintain a neutral orientation (e.g., supine, side-lying). Used to reduce the likelihood of inducing gastro-esophageal reflux. Manual percussions and vibrations are applied externally to the chest wall to exert a vibrating, shaking force to loosen sputum within the airways. Percussions are applied during both inspiration and expiration whereas vibrations are applied during expiration only. These techniques are commonly performed in conjunction with postural drainage. A percussion frequency of 15–25 Hz is considered optimal for mucus transport [96,97], however, this may not be achievable via manual techniques.
Breathing exercises	ACBT; AD	ACBT: This technique consists of cycles of relaxed controlled breathing, deep breathing (with or without inspiratory breath holds or sustained maximal inspirations), the forced expiratory technique or huffing and coughing. The precise combination of techniques often varies from individual to individual. AD: This breathing technique aims to facilitate sputum clearance via careful movement of the EPP from the lung peripheries toward the proximal, larger airways. Autogenic drainage consists of cycles of breathing that are divided into three distinct phases. These are referred to as the 'collecting', unsticking' and 'evacuation' phases. Each phase involves: 'Collecting': breathing at low lung volumes with shallow tidal volumes and gentle, short forced expirations. 'Unsticking': breathing at moderate lung volumes with medium/normal tidal volumes and moderate strength and length forced expirations. 'Evacuation': breathing at high lung volumes with large tidal volumes and stronger, longer forced expirations.
PEP therapy	Mask devices: Astra® PEP mask; Mouthpiece devices: Pari PEP®, Thera-PEP®, AeroPEP® Mouthpiece oscillatory PEP devices: Flutter®, Acapella®, bubble PEP, Quake®, RC-Cornet®	PEP-based ACTs work via the exertion of a gentle resistance during expiration. No pressure is maintained upon cessation of expiration and inspiration is un-resisted. PEP can be generated by either 'flow' or 'threshold' devices. An expiratory resistance is proposed to assist sputum clearance by: Preventing dynamic airway obstruction due to the generation of an internal protective resistance against compressive forces; Moving the EPP peripherally via increased intrabronchial pressure; Improving peripheral ventilation by opening up collateral paths (e.g., Channels of Lambert, Pores of Kohn). The addition of oscillations to PEP therapy has been proposed to enhance airway clearance by improving the viscoelastic properties of sputum. Favorable effects have been demonstrated using pulse frequencies of approximately 15 Hz.
Mechanical vibration devices	High frequency chest wall oscillation: Vest®	Mechanical vibration devices utilize mechanically generated air pressure oscillations applied externally to the chest wall, commonly via a fitted vest, to deliver similar benefits to manual percussion. A pulse frequency range of 0–20 Hz is delivered.
Acoustic impedence devices	Lung Flute®	This device utilizes vigorous exhalations into a mouthpiece to generate an oscillatory PEP of 2–2.5 cm H₂O that induces vibrations of the airways at a sound frequency of 16–25 Hz (110–115 dB). The increased expiratory effort compared with other PEP devices may be a consideration regarding its potential suitability for individuals with COPD, especially those with more severe disease.
Ventilatory support	IPV: (Percussionaire®, PercussiveTech, PercussiveNeb®) NIV	IPV: This technique involves the application of an oscillatory positive pressure (usual pressure range 10–20 cm H₂O; usual frequency range 6–12 Hz) via either a mask or mouthpiece interface. The pressure oscillations are applied during both inspiration and expiration via a continuous gas flow. IPV can be performed with simultaneous aerosol nebulization. NIV: During AECOPD, positive pressure ventilatory support during inspiration increases tidal volumes and augments inspiratory effort to unload the respiratory muscles and decrease respiratory rate.^[98] The end-expiratory pressure improves ventilation, improves gas exchange and reduces hypercapnia^[98] and may protect against early dynamic airway collapse.^[99–102] It has not been extensively studied as a form of airway clearance.
Other	Physical exercise	Exercise may benefit airway clearance by increasing the depth and rate of breathing. This may enhance the generation of airway shear forces and, in turn sputum removal, via TPGLF.

ACBT: Active cycle of breathing technique; ACTs: Airway clearance techniques; AD: Autogenic drainage; AECOPD: Acute exacerbation of chronic obstructive pulmonary disease; COPD: Chronic obstructive pulmonary disease; dB: Decibels; EPP: Equal pressure point; FET: Forced expiratory technique; GAPD: Gravity-assisted postural drainage; H₂O: Water; Hz: Hertz; IPV: Intrapulmonary percussive ventilation; MPD: Modified postural drainage; NIV: Non-invasive ventilation; PEP: Positive expiratory pressure; TPGLF: Two-phase gas-liquid flow.

Table 2. Summary of recommendations regarding airway clearance techniques in international chronic obstructive pulmonary disease management guidelines.
Study	Acute exacerbations of COPD	Stable COPD	Ref.
GOLD			[3]
ATS/ERS			[20]
COPDX	Patients who regularly expectorate sputum or those with tenacious sputum may benefit from airway clearance techniques during an exacerbation.With the exception of chest wall percussion, which was associated with a decrease in FEV1, airway clearance techniques were not associated with adverse effects.		[21]
NICE	Physiotherapy using positive expiratory pressure masks should be considered for selected patients with exacerbations of COPD to help with clearing sputum.	If patients have excessive amounts of sputum, they should be taught the use of positive expiratory pressure masks and/or the active cycle of breathing technique.	>[19]

ATS/ERS: Joint American Thoracic Society/European Respiratory Society COPD management guidelines; COPDX: Australian and New Zealand COPD guidelines; GOLD: Global Initiative for Obstructive Lung Disease guidelines; NICE: National Institute for Health and Clinical Excellence (British National Clinical Guideline Centre) COPD guidelines.