Airway clearance strategies in cystic fibrosis and non-cystic fibrosis bronchiectasis.

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Airway Clearance Strategies in Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis Eleanor Main, BSc, BA, MSc, PhD1

Lizzie Grillo, BSc, MSc1,2

1 Physiotherapy Section, RCCA, UCL Institute of Child Health, London,

United Kingdom 2 Department of Physiotherapy, Royal Brompton Hospital, London, United Kingdom

Sarah Rand, BA, BSc, MSc1

Address for correspondence Eleanor Main, BSc, BA, MSc, PhD, Physiotherapy Section, RCCA, UCL Institute of Child Health, 4th Floor, Wellcome Trust Building, 30 Guilford Street, London WC1N 1EH, United Kingdom (e-mail: [email protected]).

Abstract

Keywords

► physiotherapy (techniques) ► cystic fibrosis ► bronchiectasis ► respiratory ► breathing exercises ► inhalation therapy ► positive pressure respiration ► rehabilitation

Many patients with cystic fibrosis (CF) and non-CF bronchiectasis present with common symptoms in clinical domains that appear to benefit from airway clearance strategies. These symptoms include chronic productive cough, retention of excessive, purulent mucus in dilated airways, impairment of normal mucociliary clearance (MCC), atelectasis, breathlessness, fatigue, respiratory inflammation, fever, infection, and airflow obstruction. Airway clearance strategies may involve singular and focused interventions for the purpose of removing secretions and improving lung recruitment and gas exchange in patients with atelectasis. Strategies may also involve indirect or adjunctive interventions that facilitate or enhance effective airway clearance at different ages or stages of the disease process, for example, inhalation therapy, exercise, oxygen therapy, or noninvasive ventilation. The aim is to optimize care by selecting any one or combination of these in responding intelligently and sensitively to individual and changing patient requirements during their lifetime. Currently, a solid evidence base does not exist for airway clearance strategies in CF and non-CF bronchiectasis, and much of airway clearance clinical practice remains in the domain of clinical expertise. The paucity of evidence is partly explained by the relatively immature research machinery in allied health care internationally but is also partly to do with inadequate or inappropriate research designs. This article aims to provide an overview of the nature of, and physiological basis for, the direct and indirect airway clearance strategies in CF and non-CF bronchiectasis with reference to the best available evidence.

Postural drainage (PD) and breathing techniques have been described in the literature for more than a century as airway clearance strategies for people with difficulty clearing excessive pulmonary secretions. It is only, however, in the past 40 years that several different airway clearance devices have been developed and marketed internationally, and that some serious efforts have been made to evaluate the scientific evidence for airway clearance interventions. The global evolution of different airway clearance techniques (ACTs) has resulted in invention, modification, retention, or rejection of different methods. Certain ACTs have strong geographical

Issue Theme Cystic Fibrosis and NonCystic Fibrosis Bronchiectasis; Guest Editor: Andrew M. Jones, MD, FRCP

dominance, usually as a consequence of the origin of the technique and the strength of marketing in that country, rather than as a result of best evidence. Some ACTs involve positive airway pressures with or without airway oscillation, some are independently performed and others require electricity, physical assistance, postural, or activity modifications. Airway clearance strategies may involve direct interventions for the purpose of removing secretions and improving lung recruitment and gas exchange in patients with suppurative lung disease. Strategies may also involve indirect or adjunctive

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DOI http://dx.doi.org/ 10.1055/s-0035-1546820. ISSN 1069-3424.

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Semin Respir Crit Care Med 2015;36:251–266.

Airway Clearance Strategies in CF and Non-CF Bronchiectasis interventions that facilitate or enhance effective airway clearance at different ages or stages of the disease process, for example, inhalation therapy, exercise, oxygen therapy, or noninvasive ventilation (NIV). Underpinning these numerous ACTs is a clutch of theoretical pulmonary physiology principles which lend them credibility. Among these are “interdependence,” “pendelluft,” “equal pressure points,” “hysteresis,” “collateral ventilation,” “altered rheology,” and “two-phase gas liquid flow interactions.” The fact remains that at present, a solid evidence base does not yet exist and much of airway clearance clinical practice for physiotherapists remains in the domain of clinical expertise. The paucity of evidence is partly explained by the relatively immature research machinery in allied health care internationally but is also partly to do with inadequate or inappropriate research designs. Although there have been improvements in the design, quality, and rigor of research conducted in airway clearance strategies, these have not yet resulted in clarity for clinical practice. Ironically, in this field of research, even the gold-standard long-term randomized controlled trial (RCT) may be an inappropriate research design. This is because it does not account for the unpredictable behavior of participants who cannot easily be (and are not usually) blinded to the airway clearance treatment they are allocated. People with chronic lung conditions can develop strong preferences for the way they undertake their daily airway clearance treatments. Significant participant dropouts in four recent long-term airway clearance studies have exposed unanticipated but fundamental shortcomings in the standard RCT trial design in airway clearance physiotherapy studies.1–4 Strong patient preference, lack of blinding, and the requirement for effortful and demanding participation over long intervals are likely to continue jeopardizing research into the best airway clearance strategies for patients with chronic lung disease.5 Researchers must begin to address these problems more imaginatively in future clinical trial designs if any progress is to be made in identifying clinically effective airway clearance strategies.6 The best evidence from a plethora of early, underpowered, short-term studies, typically crossover design and 1 to 14 days in length, has been synthesized in five Cochrane reviews related to ACTs for CF, published between 2000 and 2011.7–11 All conclude that there is currently insufficient evidence to suggest superiority of any one technique over another. The earliest of these reviews, recently updated, compared airway clearance to no treatment in people with CF. The review included 96 participants in eight crossover studies (six of which were single treatments and two of which involved two and four treatments, respectively), and concluded that there was some evidence that airway clearance increased mucus transport rate. There was insufficient evidence to indicate any long-term effects.7 The British Thoracic Society, Association of Chartered Physiotherapists in Respiratory Care, Association of Chartered Physiotherapists in Cystic Fibrosis, and National Institute for Health and Care Excellence provide comprehensive guidelines on the physiotherapy approach to airway clearance Seminars in Respiratory and Critical Care Medicine

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strategies for adults with bronchiectasis (CF or non-CF). These guidelines largely comprise “Good Practice Points” from predominantly short-term studies with inadequate sample sizes. There are few clear directives from high levels or grades of published evidence. That said, experienced physiotherapists and clinicians continue to recommend the airway clearance strategies covered in this article, and any decent published evidence, where it exists, will be made explicit. This article aims to provide an overview of the nature of, physiological basis for, and best available evidence behind the direct and indirect airway clearance strategies in cystic fibrosis (CF) and non-CF bronchiectasis. This article will also suggest potential modifications in physiotherapy care necessary when managing acute exacerbations, infants or children with CF or non-CF bronchiectasis, comorbidities, or end of life care. Airway clearance strategies will be the focus of this article, but they form a limited part of the overall physiotherapy management for patients with CF and non-CF bronchiectasis. In general, physiotherapy interventions would also aim to optimize health and health-related quality of life (HRQOL) by improving or maintaining mobility and functional and exercise capacity, and assisting with breathlessness management and symptom control for people living with these chronic diseases.12,13 The important sequelae that arise from an inability to clear pulmonary mucus effectively, and in particular, any broad differences in therapeutic management between CF and non-CF bronchiectasis will also be elaborated on here.

Clinical Presentation The pathophysiology of both CF and non-CF bronchiectasis is well described and both conditions demonstrate a dramatic variability in clinical phenotype. In CF, the disease presentation will vary from mild atypical disease to severe, destructive lung disease. Similarly, disease etiology may be unknown for more than half of the patients with non-CF bronchiectasis, with disease severity and age at presentation both spanning the spectrum. Many of these patients, however, present with common characteristics in clinical domains that tend to benefit from physiotherapy. These characteristics can include progressive chronic productive cough, excessive and purulent mucus in dilated airways, impairment of normal MCC, secretion retention, atelectasis, breathlessness, wheeze, respiratory inflammation, fever, infection, airflow obstruction and chest pain, fatigue, and reduced functional capacity. It does not, from an airway clearance perspective, particularly matter what precipitates the cycle of respiratory infection, inflammation, and bronchial destruction. It is more important to deal intelligently and sensitively with individual patient needs and requirements. A one-size-fits-all strategy is not likely to work and attempts to enforce routine care are more likely to result in alienation or disengagement of patients from these potentially valuable aids which they could rely on at some point in their disease progression. Almost 50% of adults and around 30% of children with CF admit that they do not undertake airway clearance as


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recommended, and these figures are likely to be similar for non-CF bronchiectasis.14,15 The reasons for cough suppression or poor compliance with airway clearance strategies may be numerous and multifactorial, including burden of care and lack of time, or confidence in the treatment, but may also include secondary complications of the disease, for example, urinary stress incontinence in females with chronic respiratory disease.16–18 In these cases, airway clearance modalities which incorporate breathing control (BC) and avoidance of the high pressures associated with Valsalva maneuvers could be recommended. Or, for example, patients with advanced respiratory disease may have significantly deranged spinal and thoracic musculoskeletal functional anatomy as a result of chronic air trapping, hyperinflated chest walls, flattened diaphragms, and overuse of accessory muscles.19 Typically, this manifests in a barrel-shaped chest and forward protracted shoulders which not only ultimately increase the work of breathing but also create circumstances in which musculoskeletal pain can further exacerbate restricted or splinted chest wall movement. The specific challenge for physiotherapists is to address the wide variability in number, type, and severity of the symptoms and to identify and respond to the specific and changing clinical needs of patients that they care for, throughout their lifetimes. As ever in the health care management of chronic conditions, self-management and self-efficacy of individual patients are important variables.20–25 Attitudes toward illness and engagement with care vary considerably and emotional intelligence and expertise are required to identify both the appropriate strategy and the “way in” for each person.

Airway Clearance Techniques and Strategies Airway clearance strategies are considered an integral part of management in CF and non-CF bronchiectasis. In CF, ACTs have traditionally been taught as soon as a positive diagnosis has been made, which has often been in early infancy and usually in association with overt respiratory symptoms. Similarly, ACTs are commenced for non-CF bronchiectasis as soon as a positive diagnosis has been made, but the onset of the disease is more frequently in later life after a precipitating illness. In general, ACTs and strategies will be changed and adapted during the course of the chronic illness, generally progressing from techniques that are dependent on the assistance of a parent or health care practitioner in early life, to self-administered techniques that can be performed independently and portably if necessary in later life.26,27 Specialist health care services for non-CF bronchiectasis have developed later than those for CF in many countries and this delay in focus has resulted in a smaller body of published evidence for non-CF bronchiectasis. Although it is prudent to be cautious about extrapolating the evidence between the two conditions, it is clinically accepted that patients with a productive cough and evidence of mucus plugging on computed tomography (CT) could benefit from being taught a regular ACT and those individuals who have a nonproductive cough should be taught a technique to use during an exacerbation.27

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The frequency and duration of airway clearance treatments may vary in different patients both during and between exacerbations. Patients with CF or non-CF bronchiectasis are likely to receive a recommendation to undertake ACTs one or more times daily during their lifetimes. Guidelines suggest that airway clearance should continue until excess secretions are cleared.27,28 The technique that is simplest and most effective for individual patients should be selected: it is largely accepted that individual patient preference may significantly influence adherence to treatment, especially if the burden of the treatment is substantial.5,6 There are few contraindications or adverse events related to ACTs in CF and non-CF bronchiectasis. The scope and spectrum of techniques available allow for significant modifications to care which avoid individual issues that arise. For example, manual techniques may be contraindicated in the presence of unstable rib fractures, but alternatives, including positive expiratory pressure (PEP) therapy or breathing techniques are available. One commonly accepted contraindication to ACTs is frank hemoptysis, but it becomes even more important to resume regular ACTs the moment it is considered safe to do so to remove any retained blood products in the airways, and avoid the associated complications.

Airway Clearance Strategies for Babies and Children with CF and Non-CF Bronchiectasis ACTs for infants and young children with CF and non-CF bronchiectasis have a weak evidence base and can be challenging to perform. The majority of the evidence to support the use of ACTs in infants and young children is from the CF population and, in general, ACTs have been adapted from techniques developed for older patients with chronic sputum retention.29 The limited evidence on ACTs in infants and young children with non-CF bronchiectasis comes from consensus statements, and assumptions about benefit are extrapolated from assumptions about common symptomatology between the conditions.30 Age-related physiological and pathophysiological differences between children and adults, such as differences in airway mucus composition, respiratory mechanics, and lung development exist. These along with other unique aspects of development such as gastroesophageal reflux (GOR) and behavioral challenges are also important considerations when initiating ACTs in this age group.31 The international uptake of newborn screening for CF early in the millennium was relatively slow but became far more widely implemented from 2007. The United States, United Kingdom, Republic of Ireland, France, Italy, Spain, Austria, Poland, and the Czech Republic now have CF newborn screening programs either regionally or nationally as do Australia and New Zealand.32,33 This has resulted in the emergence of a novel cohort of infants in these countries who may have a diagnosis of CF but may have few, if any, overt respiratory symptoms.34 This cohort has quite reasonably created some uncertainty about the role of traditional routine daily chest physiotherapy when parents are not able to observe or appreciate any Seminars in Respiratory and Critical Care Medicine

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Airway Clearance Strategies in CF and Non-CF Bronchiectasis palpable benefit from an intervention that is not always popular.35 The uncertainty arises because several studies have suggested that despite an apparent lack of symptoms, there are demonstrable changes on CT, and bronchoalveolar lavage (BAL) studies have shown the presence of inflammatory markers and bacterial and viral pathogens in clinically asymptomatic babies with CF.36–38 Recent evidence suggests that with current care in the United Kingdom, the reductions in lung function observed in these infants at 3 months of age have largely resolved by 1 year of age and these benefits are maintained at 2 years.39 The infants who participated in this longitudinal cohort were receiving a variety of physiotherapy and airway clearance interventions, depending on the recruiting center. These ranged from modified postural drainage and percussion (mPD&P) once or twice daily, to exercise and mPD&P, to infant PEP. There were no differences between centers in terms of lung function in the first 2 years of life, suggesting that any combination of these airway clearance strategies could be successful. In the absence of firm evidence, the United Kingdom consensus guidelines currently recommend the early establishment of a physiotherapy regimen of advice and education for parents, physical activity, exercise, and ACTs.34 It may not be feasible to aim for international consensus on airway clearance strategies for newborn babies with CF because screening has not yet been universally adopted. There is likely to be a two-tier international CF newborn population, who will either present asymptomatically following screening or will present with significant symptoms sometime after birth, which will lead to a diagnosis of CF. Physiotherapy airway clearance strategies will generally need to be more determined for infants in the latter group. The most commonly used ACTs for infants and young children are mPD&P,40 infant PEP, assisted autogenic drainage (AAD), and bubble PEP. These will be discussed in more detail within relevant sections below.

Postural Drainage and Modified Postural Drainage PD was one of the first ACTs described for people with chronic respiratory disease and appeared be a successful airway clearance strategy in single case studies of patients with bronchiectasis as early as 1901.41 It is achieved by placing individuals in specific recumbent or semirecumbent positions that enable gravity to move mucus from peripheral airways in selected lung segments, to more central airways for expectoration.29 Some standard PD positions incorporate a head down tilt of approximately 30 degrees, where the head is lower than the thorax. This position prompted concerns that GOR and therefore potentially pulmonary microaspiration might be exacerbated in some adult patients and particularly in infants and young children with CF. Evidence suggests that background GOR is more common in infants and children with CF, and is twice as common in people with chronic respiratory disease including bronchiectasis, than in a healthy population.42 An early study compared the effects of standard PD with an alternative called modified PD (mPD), which used horizontal Seminars in Respiratory and Critical Care Medicine

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positions instead of head down tilt, in 20 infants with CF. Significantly more episodes of GOR (p < 0.05) were seen with PD than with mPD particularly during supine and prone positioning.43 Another study in adults, who were significant sputum producers, also suggested mPD was as useful as standard PD and was preferred by patients.44 Despite the risk of GOR, standard PD or mPD are very useful tools in the ACT armament. Two studies have demonstrated that PD is more effective than oscillating PEP (OPEP) or the active cycle of breathing technique (ACBT) alone in terms of volume of secretions cleared, and appeared to hint that gravity-assisted positions are more helpful than sitting upright for ACTs but may not require the head down tilt.44,45 These findings were not reproduced in a small study of bronchiectasis patients in Hong Kong.46 Although PD may be of significant benefit to some, others continue to find it uncomfortable, time consuming, and it may increase symptoms of breathlessness.47 It appears that for a significant minority of patients with GOR, standard PD may contribute to clinically significant exacerbation of GOR,40 and for these patients, mPD or alternative airway clearance strategies may be advisable. mPD is now used more commonly than PD in the care of children and infants with CF and non-CF bronchiectasis. When PD or mPD clearly enhances airway clearance in individual patients and there are no contraindications or side effects, they should be encouraged. If patients find PD or mPD useful in an exacerbation, the concurrent use of intermittent positive pressure breathing or NIV may help overcome any increased breathlessness with the additional benefits of PEP therapy for secretion management.26

Manual Techniques Manual techniques are also among the longest standing airway clearance strategies and include percussion (chest clapping with a cupped hand), chest wall vibrations or shaking (rhythmical chest wall compressions during expiration with fast or slow oscillations, respectively), and chest compressions (usually applied as over pressure at the end of expiration to assist cough, support expiratory maneuvers, or reduce air trapping). These techniques are typically used to both loosen secretions as well as to reduce fatigue or increase effectiveness of other airway clearance techniques. Evidence has routinely shown that a combination of PD or mPD and percussion or vibrations have been as useful as other airway clearance strategies.1,2,10,48 Both fast and slow percussion have been shown to improve sputum production significantly when used in addition to PD and forced expiration techniques (FET).49 However, manual techniques have also commonly been the least preferred ACT by patients, largely because they involve dependence on a care giver to deliver the treatment, which can be uncomfortable, inconvenient, or embarrassing and socially limiting.1,2 Historically, PD and percussion were the mainstay of ACTs in CF care, but in the last three decades, several newer and more independent airway clearance strategies have been developed which are more active and allow patients to be more independent in their daily routine.50 There may still be a significant role for this intervention in sputum producing babies and infants


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with CF or non-CF bronchiectasis, or in patients with severe disease who may find it helpful in conjunction with oxygen or positive pressure supplementation. A comparison of OPEP devices (Flutter [Scandipharm, Birmingham, AL] and Acapella [DHD Healthcare, Wampsville, NY]) and manual techniques showed that although the OPEP devices produced higher oscillation frequencies than chest wall vibration and percussion in 18 young adults with CF, chest wall vibration produced greater expiratory flow rates and a higher peak expiratory/peak inspiratory flow (PIF) ratio.51 Theoretically, the higher peak expiratory flow (PEF) rate during vibration compared with the other physiotherapy interventions would promote secretion clearance, and the frequency of vibration oscillations was within the range demonstrated to increase mucus transport. This evidence supports the physiological rationale for the use of vibration to aid secretion clearance, but patient preferences and beliefs remain powerful motivators for adherence to medical treatments.

Independently Performed Airway Clearance Strategies Active Cycle of Breathing Technique The ACBT is an airway clearance strategy, modified from the directed breathing and FET first described in the literature in 1979.52 The purpose of this technique is to produce dynamic compression and collapse of the airways downstream of the equal pressure point,52,53 creating a “pinch point” and increased turbulent airflow.54 It consists of three distinct breathing cycles performed in sequence: BC, thoracic expansion exercises (TEEs), and FET. The cycle can be repeated and the length of each component can be adapted to individual need. It can be used across many ages, and across all stages of disease. The technique is well described elsewhere and will not be repeated here in detail,55,56 but briefly, BC is described as relaxed breathing at tidal volume, performed at the patient’s own rate. TEEs are slow deep inspirations through the nose, followed by an inspiratory pause with an open glottis, and then a relaxed expiration. FETs are the principle component of the technique, consisting of a combination of one or two forced expirations interspersed with BC. The FET comprises controlled acceleration of airflow through an open glottis from mid-lung volumes to near residual volumes.56,57 The ACBT is commonly used in combination with other devices or PD. A Cochrane systematic review, comparing the clinical effectiveness of ACBT with other airway clearance therapies in CF, included 18 studies involving 375 participants. Sixteen of these studies involved an intervention period of 1 week or less (13 were single-treatment studies). There was insufficient evidence to suggest that ACBT was superior to any other ACT. ACBT was found to be comparable to other therapies in terms of patient preference, lung function, sputum weight, oxygen saturation, and number of pulmonary exacerbations11. A short-term study comparing ACBT with high-frequency chest wall oscillation (HFCWO) therapy in 10 children with CF during an exacerbation found significant improvements in lung function from ACBT and no change after HFCWO.58 In addition, a 1-year RCT involving 75 patients with CF compared five independently performed ACTs: ACBT,

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autogenic drainage (AD), PEP, Flutter and Cornet (R.Cegla GmbH & Co. KG, Monataur). There were no significant differences between these ACTs in terms of pulmonary function, body mass index, exercise capacity, and HRQOL. Of the 22 participants who did not complete the study, 13 did not like the regimen to which they had been randomized, emphasizing the importance of patient preference on adherence.4 The evidence supporting ACBT for non-CF bronchiectasis is also weak, although it is the ACT most commonly taught by physiotherapists in the United Kingdom.59 A randomized crossover study of 17 stable patients with non-CF bronchiectasis compared 4 weeks of daily ACBT with 4 weeks of daily Flutter device therapy and found they were equivalent in all outcomes.60 A Cochrane systematic review, investigating the benefits of ACTs for bronchiectasis, included five studies (51 participants), with sample sizes ranging from 8 to 20 participants.61 None of these studies involved ACBT as an intervention, but one single-treatment study, incorporating FET and PD suggested that the use of nebulized saline or terbutaline immediately before gave a significantly greater yield of sputum than did physiotherapy alone,62 providing some support for inhalation therapy as an adjunct to ACTs. A randomized crossover single-treatment study found ACBT (incorporating PD and chest wall vibration) to be superior in terms of sputum wet weight yield to the TIRE—test of incremental respiratory endurance (not well known as an ACT) in 20 patients with stable, productive bronchiectasis.63 Another single-treatment study comparing the efficacy of ACBT with Acapella in 20 adults with stable, productive non-CF bronchiectasis concluded that they were equivalent in terms of sputum weight expectorated.64 A third single-treatment study investigating the effect of using the ACBT in horizontal versus head down tilt positions found no significant difference in the wet weight of sputum expectorated in patients with non-CF bronchiectasis, but reported that patients were more breathless with head down positions.44 Finally, a short-term study comparing Flutter, ACBT and ACBT plus PD in 36 adults with stable non-CF bronchiectasis, reported that the wet weight of sputum from ACBT or Flutter in sitting was only half the volume compared with ACBT and PD.45 The benefits of PD or mPD as an adjunct to ACBT seem compelling.

Autogenic Drainage and Assisted Autogenic Drainage AD is also an independently performed breathing technique, developed in Belgium more than 50 years ago. It aims to achieve high expiratory flow from sequentially different lung volumes to assist with airway clearance from peripheral to central airways in a variety of clinical conditions including CF and non-CF bronchiectasis.56,65 Unlike ACBT, however, AD is a three-phased regimen, using controlled breathing to maximize expiratory flow, while minimizing airway closure, starting with low volume breathing at expiratory reserve volumes. When secretions are heard or felt, cough is suppressed but a series of higher volume breaths are taken, again without cough. The final phase involves large volume breaths near vital capacity, before FET or huffs are used to clear secretions. The maximal expiratory flow is hypothesized to produce shearing forces to move secretions and the sequential change in lung volumes theoretically moves the equal Seminars in Respiratory and Critical Care Medicine

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Airway Clearance Strategies in CF and Non-CF Bronchiectasis pressure point more distally, with the aim of improving flow in the smaller airways. The effort required in mastering the ranges and control of volume and flow, and in being sensitive to auditory and vibratory cues of secretions in the airways is significant, and AD is therefore not considered suitable for young children. AAD is the equivalent option for younger children but is not evidence based and requires the assistance of a parent or caregiver. This technique has some popularity in the United Kingdom, Europe, and Canada, as an independent ACT, but the evidence is limited in both CF and non-CF bronchiectasis. In CF, many of the AD studies have significant methodological problems and results are mixed. Short-term studies in CF have shown AD to be equivalent to Flutter in terms of lung function, but less effective in reducing sputum viscoelasticity.66 It was also more effective than cough alone, but produced less sputum and was less likely to elicit bronchospasm than high pressure PEP,67 and it was equivalent to PD in terms of sputum yield, but less likely to elicit desaturation.68 A 2-day crossover study comparing AD with ACBT concluded AD was as effective as ACBT but cleared sputum faster.69 Another short-term study found that sputum yield from AD could be significantly increased if preceded by saline inhalation delivered by nebulizer or intrapulmonary percussive ventilation (IPV).70 A longer term study over 12 months in the United Kingdom, comparing ACBT, Flutter, PEP, Cornet, and AD, suggested clinical equivalence between methods in terms of all the outcomes measured.4 In addition, a Canadian 24-month crossover study published in the same year, compared AD with PD&P in 36 adolescent patients with CF. Both groups showed similar improvements in lung function over the first 12 months but the number of dropouts at the 12-month crossover point, precluded continuation of the study. There was a marked preference in this population for AD, although clinical superiority was not demonstrated.2 The authors argued reasonably that ACT adherence would be more likely if patients preferred the technique they were using.6,71,72 The AD evidence in non-CF bronchiectasis is limited with a single-treatment study showing AD to be more effective than the control in clearing secretions in 13 patients with bronchiectasis.73 Another study compared the effects of AD with ACBT for a period of 20 days in 30 patients with chronic obstructive pulmonary disease (COPD). Patients who used AD had more significant improvements in PEF, oxygen saturation, and chronic hypercapnia.74 The combination of controlled breathing to reduce airway collapse and high PEFs might therefore be an important ACT choice for patients with non-CF bronchiectasis for whom air trapping, desaturation, or bronchial reactivity are known features. AAD is an adaptation of AD for infants and young children not yet capable of carrying out the technique independently.29 The aim of AAD is also to achieve an optimal expiratory flow progressively through all generations of bronchi without causing dynamic airway collapse. In infants, AAD is achieved by the therapist or trained care giver placing their hands over the child’s chest and, using the child’s own breathing pattern, manually increasing the expiratory flow velocity by gentle external compression. In theory, this prolongs expiration Seminars in Respiratory and Critical Care Medicine

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toward residual volume.29 A small single study has suggested that GOR is not provoked during AAD treatment.75 There is currently no objective evidence to support any airway clearance benefits of AAD in infants and young children.

Device-Dependent Techniques PEP and Infant PEP Therapy The use of PEP as an airway clearance strategy is theoretically beneficial in several respects. PEP devices usually include a one-way valve allowing unrestricted inspiratory effort, with a variable fixed resistance to expiration through another flow or threshold limited valve or orifice. The patient breathes out against the backpressure, producing positive airway pressure which in theory holds the airways open during expiration, stabilizing, and splinting the airways. This hypothetically promotes airflow through the peripheral airways, preventing premature airway closure and theoretically improving gas mixing, reducing gas trapping in the lung, and facilitating airway clearance.76–78 This is thought to help mobilize the secretions to the larger airways. There are a variety of commercially available PEP airway clearance devices, both with and without an oscillatory airflow component. The PEP mask technique uses a modifiable orifice resistance applied during expiration, usually through a mask attachment. The PEP mask is hypothesized to promote interdependence between the alveoli, facilitate collateral ventilation, and encourage recruitment of closed airways by temporarily increasing functional residual capacity during expiration. Patients usually perform the technique by actively expiring against the resistance for 5 to 20 tidal volume breaths, aiming to generate a mid-expiration airway pressure between 10 and 20 cm H2O. The PEP mask can be, and often is, combined with other airway clearance strategies such as FET or PD or ACBT (during the TEE component). There are several single intervention or very short-term studies that have shown PEP to be as effective as other ACTs.78–81 In several longer term studies by a Canadian research group, involving patients with CF, PEP was reported to be superior to PD and percussion,82 OPEP via the Flutter device83 and HFCWO.3 These findings have not yet translated into unequivocal guidance in favor of PEP by a Cochrane systematic review of PEP therapy for CF.8 In this review, there were no significant differences between PEP and other ACTs in single treatments or treatments undertaken for < 3 months in terms of forced expiratory volume in one second (FEV1). Longer term studies had equivocal or conflicting results regarding effects of PEP on FEV1. However, in studies with an ACT intervention period exceeding 1 month, any measures of participant preference were always in favor of PEP.8 The evidence for PEP in patients with bronchiectasis is very limited. In a recent Cochrane review evaluating ACTs for nonCF bronchiectasis, there were no studies evaluating nonoscillatory PEP devices. In a small single intervention study involving eight patients, Flutter or PEP for up to 40 minutes in a single session did not appear to change ciliary or cough transportability of bronchial mucus in patients with bronchiectasis.84


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Infant PEP is now relatively commonly used as an ACT for babies with CF. Infant PEP is delivered via an appropriately sized facemask, which is held in place over the infant’s nose and mouth and is commonly performed in combination with physical activity, for example, bouncing on a gym ball, to facilitate a natural modulation of lung volumes. Infant PEP is primarily aimed at altering the ventilation distribution in infant’s lungs as well as creating a positive expiratory airways pressure to assist in “splinting” the airways open. Twice daily infant PEP was compared with twice daily mPD in 26 newborns with CF in an RCT over 12 months.85 Oxygen saturations were significantly higher in the PEP group compared with the mPD group (98.1 vs. 96.7%, p < 0.05) and the incidence of GOR was approximately 20% in both groups, which was similar to that occurring naturally in infants with CF.86 The authors concluded that infant PEP was safe, effective, and there was greater preference for it over mPD.

Oscillating PEP Including Bubble PEP PEP devices that contain an expiratory oscillatory component such as the Acapella, RC Cornet, Flutter, Aerobika (Trudell Medical International, Ontario, Canada), Lung Flute (Medical Acoustics, Buffalo, NY), and Quake (Thayer Medical Corporation, Tucson, AZ) are all theoretically useful for patients with tenacious secretions, as the frequency of oscillations are hypothesized to loosen secretions and reduce mucus viscoelasticity.9,66 They are similar to the PEP device, in that they involve breathing against an expiratory resistance, but the resistance is intermittent or interrupted by a ball valve, lever, or collapsible tubing, such that oscillations of variable frequency (depending on device or use) are transmitted to the airways during the expiratory cycle. An airflow bias is created as the oscillations increase the expiratory airflow.87 In CF, there is single-treatment evidence that Flutter is as effective as AD in terms of sputum volume and spirometry, but the frequencies and amplitudes of applied oscillations in the Flutter also decreased mucus viscoelasticity, theoretically improving MCC and cough clearance of secretions.66 A Cochrane systematic review updated in 2006 included four studies that all incorporated the Flutter OPEP device.8 Two of these, conducted over a period of 4 weeks or less found no differences in outcomes. One of these was a 2-week study comparing PEP versus Flutter,88 the other was 4 weeks of PEP versus PD versus Flutter.89 In the remaining two studies which lasted at least 12 months, comparisons between PEP and Flutter resulted in conflicting advice, one in favor of PEP in adolescents with CF83 and the other in favor of Flutter in adults with CF.90 Another long-term study published since this review found no significant differences in outcomes between ACBT, AD, PEP, and the two OPEP devices, Flutter and Cornet.4 In non-CF bronchiectasis, the only OPEP devices that have appeared in the literature to date are the Flutter and Acapella devices, which appear to have similar performance characteristics.91 A very recent systematic review of OPEP devices for non-CF bronchiectasis included seven studies, all with relatively small sample sizes, representing 146 participants. Five of these studies were single-treatment studies,45,64,92–94 and

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the remaining two were conducted over a period of 4 weeks60 and 6 months, respectively.95 The review suggested that in stable non-CF bronchiectasis, OPEP therapy was associated with improvements in sputum expectoration and quality of life measures compared with no treatment. Compared with other ACTs, the effects in terms of sputum expectoration, lung function, gas exchange, and symptoms were equivalent.96 For older infants under the age of 4 years who no longer tolerate infant PEP but who are unable to progress to other forms of ACT, “bubble PEP” may be a useful OPEP bridging ACT. The child blows through tubing which is immersed to a depth of at least 10 cm of water. The height of water in the bottle provides the threshold resistance to expiration and the bubbling effect produces an oscillatory effect in the airways. Bubble PEP is a threshold resistor type of PEP in which the expiratory pressure remains constant once the tubing diameter is 8 mm, independent of tube length.97 There is no published evidence to support the use of bubble PEP in CF or non-CF bronchiectasis.

High-Frequency Chest Wall Oscillation HFCWO is administered by an inflatable vest that fits over the thoracic cage, attached to an air pulse generating compressor. The rapid inflation and deflation of the jacket creates airway oscillations at the chest wall between 5 and 25 Hz. Initial evidence suggested that HFCWO was as effective as other ACTs for patients with CF.98–100 However, recent studies have suggested that HFCWO clears significantly fewer secretions than other techniques in an infective exacerbation,101 and could increase the frequency of exacerbations and shorten the time to an exacerbation when compared with PEP therapy over the long term.3 In non-CF bronchiectasis, a recent Turkish crossover study comparing 5 days of HFCWO with 5 days of PD, vibration and percussion in patients with primary ciliary dyskinesia, found no differences between these airway clearance strategies.102 Another Italian study compared HFCWO with a variety of other airway clearance strategies and a control group who had no intervention over 15 days. Both HFCWO and the other ACTs performed better than the control group for all outcomes measures. Some improvements in dyspnea were reported in the HFCWO group, but the heterogeneous ACT comparison group makes this outcome difficult to interpret.103 Improvements in dyspnea were also reported in an American study involving four consecutive HFCWO treatments for patients during an acute exacerbation.104

Noninvasive Ventilation and Cough Assist Devices Less frequently, PEP therapy may be combined with positive inspiratory pressure delivered via NIV as continuous positive airway pressure, bilevel positive airways pressure, and intermittent positive pressure ventilation devices. These options are usually not used as primary ACTs but are reserved for patients who have very severe disease, hypoxia, inspiratory muscle weakness, or dyspnea and are therefore less able to perform airway clearance easily without assistance. They can be very useful adjuncts to other ACTs, especially when people have difficulty expectorating.105–109 Seminars in Respiratory and Critical Care Medicine

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Airway Clearance Strategies in CF and Non-CF Bronchiectasis There is some evidence that NIV might slow or reverse the decline in lung function in people with advanced CF, and that it is more effective in conjunction with oxygen than oxygen alone for advanced disease.107,110 There is also some evidence of improvement in functional capacity, lung function, respiratory rate, and oxygen saturation when children or young adults with CF and pulmonary impairment undertake treadmill walking with NIV.111 Devices that combine elements of both positive and negative pressures throughout the breathing cycle with or without airway oscillations, such as IPV, may also be useful in airway clearance but are less commonly used.112 There is no evidence that cough assist devices are of any benefit in either of these patient groups at all. The pathophysiology of CF or non-CF bronchiectasis, which does not typically include respiratory muscle weakness suggests that this form of treatment is unlikely to be helpful, except perhaps at end-stage disease, when fatigue and weakness may be important features.113

Exercise and Pulmonary Rehabilitation as Airway Clearance Strategies Physical activity and exercise have become key components in the management of individuals with CF, in particular, and increasingly in patients with non-CF bronchiectasis. Exercise is hypothesized to enhance MCC through several physiological pathways.50 A Cochrane systematic review concluded that the addition of exercise to airway clearance significantly improves lung function compared with airway clearance treatment alone in individuals with CF.114 The physiological mechanisms by which exercise acts on MCC remain unclear but may be due to the increase in ventilatory demand during exercise, which is met by increases in tidal volume and respiratory flow.115 This increase in ventilation (V′E) and PEF has the potential to increase mechanical clearance of secretions from the airways. It is proposed that if PEF is greater than the PIF during exercise, the annular flow of mucus toward the oropharynx may be augmented through two-phase gas liquid flow.116 Moderate intensity exercise may also increase the water content of mucus in people with CF as it inhibits the sodium conductance in luminal nasal respiratory epithelium; potentially further explaining benefits in terms of ease of expectoration.117 An increase in airway surface hydration occurs following exercise due to the creation of an osmotic stimulus associated with high levels of V′E.118 The increase in V′E may also have the potential to affect mucus rheology due to the associated shear forces, which have been shown to reduce mucus viscoelasticity.66 The physical body movements associated with exercise may have an additional effect on mucus rheology. A 3-day crossover study investigated the effects of a single bout of moderate intensity exercise (treadmill or cycle exercise) in 14 adults with CF on V′E, PEF, expiratory flow bias ratio (PEF:PIF), sputum properties, and subjective ease of expectoration.115 There was a subjective improvement in ease of expectoration during both treadmill and cycle exercise. The V′E, PEF, and PEF:PIF were all significantly higher during both treadmill and cycle exercise compared with baseline measurements with a trend toward the highest values during cycle Seminars in Respiratory and Critical Care Medicine

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exercise. The PEF:PIF ratio did not meet the > 1.10 threshold believed to be necessary for the promotion of annular flow from the airways to the oropharynx and authors hypothesized that expiratory airflow bias did not contribute to the ease of expectoration reported by the participants. There were significant changes in sputum mechanical impedance following treadmill exercise compared with the control group, suggesting perhaps that the body oscillations associated with running (rather than cycling) may have reduced sputum viscoelasticity, in a similar way to other oscillatory PEP devices.66 In another small study comparing the effects of treadmill exercise with PEP and OPEP in adults with CF, treadmill exercise produced a PEF:PIF of only 0.9, whereas OPEP produced a PEF:PIF of 1.13 which was considered sufficient to mobilize secretions proximally.119 Both the treadmill and OPEP significantly reduced mucus viscoelasticity. Further research is required to fully confirm the physiological effects of exercise in CF, but it appears that exercise in CF has the potential to affect airway clearance in addition to the welldocumented improvements in fitness, HRQOL, and positive effects on lung function. Pulmonary rehabilitation refers to a multidisciplinary package of care that may be offered to people with chronic lung disease and usually includes patient education, exercise training, psychosocial support, and nutritional intervention and evaluation for oxygen supplementation.120,121 There is reasonable evidence to show that exercise and/or pulmonary rehabilitation are both safe and effective in CF and non-CF bronchiectasis, and have positive benefits in terms of improving dyspnea, fatigue, exercise tolerance, peripheral muscle dysfunction, and quality of life, which may be enhanced by the addition of inspiratory muscle training.114,122,123 Although the exercise training component of pulmonary rehabilitation is not considered to be an ACT in its own right, it may play a useful role in supplementing airways clearance in some individuals, especially if adherence to their normal ACT is poor.81 However, it appears that pulmonary rehabilitation in isolation is not as effective as physiotherapy and should not replace it as an airway clearance strategy.124,125 Nonetheless, if exercise prescription is well calibrated for individuals, there is an expectation that tidal lung volumes during activity would increase significantly and may enhance expiratory airflow to mobilize secretions and promote clearance of these from the smaller airways. This may be enhanced if patients are encouraged to cough and clear their chest during exercise and activity or regular and timed FETs are included throughout exercise to optimize this. During exacerbations, dyspnea may preclude exercise as an effective form of airway clearance and may need adapting, either with supplemental oxygen or with NIV.26

Inhalation Therapy Inhalation therapy, including humidification and the use of mucoactive agents such as dornase alfa (DNase) and hypertonic saline (HTS) are now integral components of airway clearance strategies for individuals with CF and non-CF bronchiectasis.126 The aim of mucoactive inhalation therapy is to prevent sputum retention and aid MCC. There have been


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Humidification Simple measures of systemic and targeted hydration of the airways can optimize airway clearance in patients with CF and non-CF bronchiectasis. Mucosal function is reported to require optimal conditions of 37°C and 100% relative humidity.130 The effects of a cold-water jet nebulizer humidification system in combination with PD in adults with non-CF bronchiectasis increased sputum wet weight yield by a median of 6 g ( 9 to 15.5 g) when compared with PD alone.131 A recent study reported that tracheobronchial humidification via a nasal interface at a flow rate between 20 and 25 L/ min (warm air fully saturated at 37°C), in 10 adults with nonCF bronchiectasis resulted in a significant enhancement of MCC and this was sustained over a 6-hour monitoring period. Acute (3 hours) and short-term (3 hours per day for 6 days) clearance effects were assessed using a tracheobronchial radioaerosol retention technique.132 Mouse models have suggested that airway surface dehydration leads to persistent neutrophilic airway inflammation with increased mucus production and resultant emphysema.133 In a prospective single-center open-labeled placebocontrolled study, 108 patients with moderate to severe COPD and bronchiectasis were either randomized to daily humidification via the Optiflow nasal cannula system (Fisher & Paykel Healthcare Limited, Berkshire, United Kingdom) for 2 or more hours per day (humidified air, fully saturated at 37° C at a flow rate of 20–25 L/min) or to usual care. Patients on long-term humidification had significantly fewer exacerbations (18.2 vs. 33.5 days, p < 0.05), increased time to first exacerbation (median 52 vs. 27 days, p < 0.05) and a nonsignificant reduction in exacerbation frequency (2.97 per patient per year vs. 3.63 per patient per year, p > 0.05).134 There have been no studies investigating the effects of humidification alone in CF. This is possibly due to differences in the pathophysiology of CF compared non-CF bronchiecta-

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sis, such that humidification alone would be insufficient to alleviate and restore the depleted airway surface liquid (ASL) height which is a key factor in secretion retention in CF. Appropriate humidification is a potentially useful adjunctive component in the management of individuals with CF and non-CF bronchiectasis and should be considered as part of the airway clearance management of these individuals.

Mucoactive Agents Dornase Alfa DNase is a genetically engineered version of a naturally occurring enzyme, which was developed with the sole purpose of reducing the viscoelasticity of sputum by breaking down DNA released by neutrophils during airway inflammation.135 DNase is routinely and commonly used in CF clinical practice to aid airway clearance. A Cochrane review concluded that the use of DNase over both a 1-month and 6-month period is associated with an improvement in lung function in individuals with CF.136 Longer term treatment over a 1-year period in CF participants aged 1.1 to 24 years significantly improved FEV1 (median increase of 7.3% in the treatment group compared with 0.9% in the placebo group p < 0.05).137 Current clinical guidelines recommend the use of DNase to facilitate airway clearance in individuals over the age of 6 years with CF. Pilot data have supported the use of DNase in younger patients but further evidence is required to establish if the early initiation of DNase treatment in infants and young children has the potential to stabilize lung function over time.138 A recent review which compared the clinical characteristics of children and young adults with CF in the United States and the United Kingdom reported that 77.2% of United States versus 35.4% of United Kingdom patients < 18 years routinely use DNase and 75.2% of United States versus 51.9% of United Kingdom patients > 18 years used DNase.139 These differences may reflect the differences in health care provision in the United States and United Kingdom but did not translate into differences in lung function outcomes between the two countries. DNase is not currently used routinely in non-CF bronchiectasis. There have been two studies investigating the effects of DNase in non-CF bronchiectasis.140,141 In the first of these, 61 adults with non-CF bronchiectasis were administered 2.5 mg DNase, either once or twice daily, or placebo for 14 days.141 DNase was well tolerated but no significant change in any of the outcome variables was shown. In fact, when non-CF bronchiectasis sputum was incubated with DNase in vitro, the sputum transportability index significantly reduced from 26 (incubated with saline) to 13 (p ¼ 0.003) suggesting that the sputum was less transportable and therefore potentially more difficult to remove. In the later study, which was larger and longer, 349 adult participants with nonCF bronchiectasis were randomized to receive 2.5 mL DNase or placebo twice daily for 24 weeks.140 Pulmonary exacerbations were more frequent in the DNase group (0.66 exacerbations per 168 days) compared with the placebo group (0.56 exacerbations per 168 days) and FEV1 decline was greater in the DNase group ( 3.6% decline) compared with Seminars in Respiratory and Critical Care Medicine

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significant advances in the understanding of the mechanisms of action of these agents and attempts have been made to classify mucoactive drugs127 as true mucolytics (work by thinning mucus), expectorants (work by inducing cough), and mucokinetics (increase mucus transport within the lungs), but in practice, these drugs probably work through several of these mechanisms simultaneously rather than in isolation.128 There are an increasing number of agents available to clinicians and the challenge is to identify the combination of agents that are most likely to be effective for each individual based on their specific pathophysiological profile, mucus production, and type, whether they are exacerbating or not, whether they have CF or non-CF bronchiectasis and the published evidence. Incorporating inhalation therapy into an individual’s therapeutic routine should also involve careful consideration of the timing in relation to ACTs and the delivery system. People with CF and non-CF bronchiectasis have distinct pathophysiological characteristics and responses to inhalation therapy. The therapeutic evidence base for non-CF bronchiectasis cannot simply be adopted from that developed for CF.129

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Airway Clearance Strategies in CF and Non-CF Bronchiectasis the placebo group ( 1.7% decline). The results of these two studies are in stark contrast to that of the evidence for the efficacy of DNase in CF patients and as a result DNase is not routinely used or recommended in non-CF bronchiectasis.142

Hypertonic Saline HTS is a sterile salt water solution usually at concentrations between 3% and 10%, usually delivered via a nebulizer in volumes between 3 mL and 10 mL.143 HTS is aimed at changing the physiochemical properties of sputum in people with hypersecretion, making it less viscous and easier to clear.142 The ciliary transport rate of mucus from patients with CF and non-CF bronchiectasis was doubled by increasing the sodium chloride content on mammalian ciliated respiratory epithelium (mucus-depleted bovine trachea), most likely via the mechanism of increasing the sputum osmolality and changing its rheology.144 For these reasons, HTS is currently used in both the CF and non-CF clinical populations. HTS has been shown to accelerate MCC in the CF airway and is recommended for use in the CF population.143,145 Significant improvements in lung function, HRQOL, and ease of expectoration with short- and long-term use of HTS have been reported in individuals with CF aged 6 years and older.143,146,147 Single-dose safety and tolerability of 7% HTS and 3% HTS in infants and toddlers with CF have been reported,148,149 and recently, the short-term tolerability, adherence, and safety of 7% HTS in infants and toddlers with CF aged 12 to 30 months in a three-center open label 14-day trial have been confirmed.150 The treatment group received nebulized 7% HTS twice daily for 48 weeks and the control group received 0.9% isotonic saline (ITS). The authors concluded that HTS was well tolerated with high treatment adherence in this short period of time. However, there were no significant differences in respiratory symptom scores, infant lung function, cough, pulmonary exacerbation rates, or antibiotic treatment days between the two groups and further research is on-going to establish the effects of HTS in this age group. Two studies in adult populations have assessed the effectiveness of HTS in non-CF bronchiectasis but have produced conflicting results.151,152 The first was a single-blind randomized crossover trial study in which 28 patients with nonCF bronchiectasis received a once daily 4 mL administration of either 7% HTS or 0.9% ITS over a 3-month period. Significant improvements in FEV1% change (15.1 vs. 1.8%) and FVC% change (11.23 vs. 0.72%) and nonsignificant changes in HRQOL scores in favor of HTS were reported. Improvements in sputum viscosity and ease of expectoration were also reported, but data were not published.151 Conversely, a randomized double-blind parallel trial compared 6 mL of either 6% HTS or 0.9% ITS administered twice daily via a nebulizer for 12 months in 40 adults with non-CF bronchiectasis. Data were collected at 3, 6, and 12 months. There was a significant decrease (p < 0.05) in both groups in the number of positive sputum cultures on completion of the trial. There were no significant differences in HRQOL, number of exacerbations, hospital admissions, or hospital days over the 12-month period between the two groups. There were Seminars in Respiratory and Critical Care Medicine

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also no significant differences in cough frequency, lung function, or self-reported adherence to the therapy. The authors concluded that HTS did not confer any clear benefit over ITS in patients with physiologically mild disease.152 The differences in outcomes between these two studies are most likely to be due to the differences in intervention length (3 vs. 12 months) or disease severity (FEV1% predicted: 66.1% vs. >80%), but unlikely to be explained by the HTS concentrations which were very similar. National guidelines from several countries on the management of non-CF bronchiectasis have not included HTS on the basis that there is currently insufficient evidence to make positive recommendations.27,153 The mechanism of action for HTS may be different between those with CF and those with non-CF bronchiectasis and differences in response to HTS may be attributable to the electrolyte content and rheology of CF sputum, which differs from that of non-CF sputum. Hyperosmolar agents, particularly HTS, do however continue to be used for non-CF bronchiectasis in clinical practice and patients should be assessed individually for their suitability and response to the treatment. Further research is required to investigate the effects of HTS in individuals with more severe non-CF bronchiectasis lung disease. Mannitol Inhaled dry powder mannitol, which was developed initially as a bronchial challenge agent in asthma is increasingly being used as an alternative mucoactive inhalation therapy in CF and non-CF bronchiectasis.154 Mannitol is a naturally occurring six-carbon monosaccharide which, when inhaled, creates a change in the osmotic gradient, leading to movement of water into the airway thereby hydrating the ASL and enhancing MCC.155,156 One of the key benefits of mannitol is that it can be administered without the use of cumbersome and often time-consuming nebulization devices as it is inhaled through a dry powder inhaler (DPI) system. This may not be the treatment of choice for individuals who demonstrate an asthmatic element to their lung disease, as hyperosmolar agents can desiccate airway inflammatory cells, disrupting the cell membrane and causing release of bronchoconstricting and proinflammatory mediators.154 A bronchoconstriction trial should be undertaken with spirometry measurements before and after administration of the first dose.27 Mannitol was licensed for use in the CF adult population in Europe in 2011 and is currently being used for adults with mild to moderate CF lung disease only. There is insufficient evidence at present to recommend its use in children < 18 years. Pooled data from two large randomized controlled phase III multicenter trials performed over a period of 26 weeks reported sustained improvements in FEV1 (73.42 mL, 3.56%, p < 0.001) and a 29% (p < 0.05) reduction in the incidence of pulmonary exacerbation following a twice daily 400 mg dose of inhaled mannitol in adults with CF.157 There was also some indication of positive benefit of mannitol on MCC, with sputum weight 30 minutes after mannitol measuring 3.0 versus 1.1 g after a control dose (p < 0.0001), and at week 14, sputum weight after mannitol and control doses


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was 2.0 and 1.0 g, respectively (p ¼ 0.006). The improvements in FEV1 seen in adults were irrespective of DNase use but were not replicated in children (6–11 years) or adolescents (12–17 years) with CF. A recent Cochrane review concluded that inhaled mannitol could delay the time to first exacerbation in patients with non-CF bronchiectasis. In patients with near normal lung function, however, lung function did not change dramatically with mannitol and adverse events were more frequent when compared with placebo.154 In a 52-week double-blind RCT of 461 adults with non-CF bronchiectasis, the administration twice a day of inhaled mannitol 400 mg was compared with a control of inhaled mannitol 50 mg.129 Exacerbation rate was not significantly reduced between groups, but time to first exacerbation was increased on mannitol (hazard ratio, 0.78; p ¼ 0.022). Sputum weight over 24 hours decreased progressively over the course of the study in both treatment arms but remained higher in the mannitol arm than the control arm throughout.

Order of Medications and Timing Mucoactive agents have specific mechanisms of action and the order and timing of administration in relation to other airway clearance strategies may have significant effects on efficacy. Accepted clinical practice in terms of DNase timing in CF is that it should be nebulized at least 30 minutes before ACTs for effective airway clearance, based on the evidence that DNase makes sputum more pourable within 30 minutes.135 At least 1 hour should be left between nebulized antibiotics and nebulized DNase to avoid denaturation of the protein structure of rhDNase.158,159 Alternative timings have been suggested, however, a recent Cochrane review concluded that the current evidence from a small number of CF studies does not indicate that inhalation of DNase after airway clearance is more or less effective than the traditional recommendation of inhalation 30 minutes before airway clearance.160 The clinical trials which demonstrated clinical efficacy of HTS for patients with CF all delivered the medication before airway clearance therapy. As a result, the currently accepted clinical practice for nebulized HTS in CF is that each dose is nebulized immediately before airway clearance therapy.50 Alternative timing regimens, such as the administration of HTS after ACT, have been suggested and are empirically used in clinical practice. A Cochrane review has however found no current evidence to indicate that alternative timing regimens are any more effective than the current practice, and advised that patients should continue to nebulize HTS before ACT.161 In addition, there is no evidence to recommend nebulizing HTS at any specific time of day in CF, so the current advice is to nebulize morning and evening if twice daily treatment is recommended, and if only one daily dose is required, it can be administered whenever convenient and best tolerated.161 There are no studies pertaining to the timing of nebulized HTS in the non-CF bronchiectasis population. Mannitol administration is currently recommended before airway clearance therapy.126 Mannitol is believed to have a rapid treatment effect in the airways and the effect on MCC is

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diminished within 24 hours.162,163 It has therefore been suggested that mannitol should be inhaled twice daily for a sustained effect on mucus clearance.164 Effective drug administration via a DPI depends on the device resistance and adequate ( 45 L/min) inspiratory flows and volumes generated by the user. Although it has been hypothesized that patients may struggle to achieve these volumes, Elkins et al investigated the mean inspiratory volume (VI) and flow in a small number of CF and non-CF bronchiectasis patients using a DPI. The mean VI of CF and non-CF bronchiectasis patients was 1.83 0.97 and 2.08 0.5 L, respectively, and a mean PIF of 75.5 27.2 and 78.6 11.2 L/min, respectively. The authors concluded that the DPI investigated allowed for adequate inspiratory flow and volume for dispersion of dry powder mannitol in these two patient groups.165,166

Inhalation Therapy Delivery Systems and Adherence There are some important factors that should be taken into account when deciding on the delivery device. These include the drug dosage, the specific characteristics of the drug being administered such as particle size, aerosol density, and airflow speed, and patient factors such as severity of lung disease, age, cognitive and physical abilities, respiratory rate, tidal volume, and adherence with treatments.71,167 Knowledge of inhalation therapy medications will assist the prescriber in choosing the best device for the patient. The success of inhalation therapy is highly dependent on indication, the administration device and the inhalation technique. Initiating inhalation therapy can also be challenging particularly in the pediatric population and failure at this stage can potentially affect future adherence so should be undertaken with great care.50 Poor adherence with prescribed treatments has been identified as a leading cause of treatment failure and monitoring adherence to prescribed therapy has been identified as a priority for health care professionals.168,169 Technological improvements have reduced nebulizer device inhalation times considerably; however, adherence to inhalation therapy has remained poor.170 Patients now have a choice of systems to use as advances in nebulizer technology have led to the availability of conventional air compressor systems and newer generation systems, which include features such as breath adaptive aerosol delivery and vibrating mesh technology which are faster, more portable, and quieter. These new devices may assist in improving adherence and reducing the burden of care for patients.170 Self- and clinician reporting of adherence does not provide accurate measurement of adherence when compared with electronic monitoring. The incorporation of electronic monitoring within some of the newer nebulizer devices allows HCPs to download information on treatment time, duration, and dose completion, providing accurate and detailed longitudinal adherence data which can help guide therapy.171 Appropriate cleaning and maintenance of nebulizer devices is imperative to avoid bacterial contamination of the equipment, to decrease the potential risk of acquiring pathogens and to ensure efficiency of the device. Patients, parents, and care givers should be provided with regular and comprehensive education and training regarding cleaning and Seminars in Respiratory and Critical Care Medicine

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Airway Clearance Strategies in CF and Non-CF Bronchiectasis sterilization and practices should be reviewed on a regular basis.50

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1999;14(6):1418–1424 14 O’Donohoe R, Fullen BM. Adherence of subjects with cystic

Conclusion 15

Airway clearance strategies are a key component in the management of individuals with CF and non-CF bronchiectasis. It is clear that although the evidence base for airway clearance strategies is not yet as secure or robust as it should be, the palette of ACTs is broad and likely to accommodate the wide variety of clinical presentations during the different ages and stages of these disease processes. With effort and imagination, the universal individualization of airway clearance routines is feasible by judicious combination and interspersing of different direct and adjunctive techniques to deal with specific and changing requirements in different patients. It is obviously essential to maintain an acute awareness of the secondary complications associated with CF and non-CF bronchiectasis as well as the pitfalls of adherence and preference in recommending airway clearance strategies and to work closely with patients and their families to optimize management of their symptoms.

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Nontuberculous Mycobacteria in Noncystic Fibrosis Bronchiectasis.

Cystic fibrosis and non-cystic fibrosis bronchiectasis.

Lung clearance index in adults with non-cystic fibrosis bronchiectasis.

Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Imaging in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Global impact of bronchiectasis and cystic fibrosis.

Defining severity in non-cystic fibrosis bronchiectasis.

[Non-cystic fibrosis bronchiectasis: diagnosis and treatment].

Aerosolized antibiotics for non-cystic fibrosis bronchiectasis.

Statins for non-cystic fibrosis bronchiectasis.

Antimicrobial treatment of non-cystic fibrosis bronchiectasis.

The microbiome and emerging pathogens in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Role of vitamin D in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Neutrophilic Bronchial Inflammation Correlates with Clinical and Functional Findings in Patients with Noncystic Fibrosis Bronchiectasis.

Matrix metalloproteinases vary with airway microbiota composition and lung function in non-cystic fibrosis bronchiectasis.

Mucociliary clearance techniques for treating non-cystic fibrosis bronchiectasis: Is there evidence?

Inhaled antibiotics in Cystic Fibrosis (CF) and non-CF bronchiectasis.

Children with recurrent pneumonia and non-cystic fibrosis bronchiectasis.

Mycobacterium avium complex infection in non-cystic fibrosis bronchiectasis.

Adult non-cystic fibrosis bronchiectasis is characterised by airway luminal Th17 pathway activation.

New Developments in Cystic Fibrosis Airway Inflammation.

MicroRNA Expression in Cystic Fibrosis Airway Epithelium.

Mortality in non-cystic fibrosis bronchiectasis: a prospective cohort analysis.