Criteria for enhancing mucus transport: a systematic scoping review

Diagnosis of tuberculosis is a critical component of the WHO End TB Strategy [1]. However, obtaining a sputum sample in unproductive PTB (pulmonary tuberculosis) subjects remains challenging [2]. Improved non-invasive sputum collection interventions have the potential to increase diagnostic performance using available laboratory testing when compared with costly new diagnostic methods [2].

Efficient mucus clearance is needed for respiratory health and requires a coordinated system of epithelial water and ion transport, mucin synthesis and secretion, cilia action and cough [3, 4]. Therefore the regulation of these processes influences mucus clearance or transport.

Diseases which result in excessive or chronic secretion retention have prompted the investigation of numerous physiotherapy techniques and devices for the purpose of mucus clearance [5‐11]. Physiotherapy techniques used for secretion clearance include positioning, percussion, vibration and shaking, breathing techniques, autogenic drainage and active cycle of breathing technique [6, 7]. Respiratory devices, namely positive expiratory pressure, high frequency chest wall oscillation, oral high frequency oscillation, intrapulmonary percussive ventilation, incentive spirometry, flutter, acapella, cornet, and the relatively new addition lung flute, are some examples of devices which have been used to augment clearance [7, 8, 10, 11].

Limited data is available on the effectiveness of various physiotherapy strategies and there is uncertainty regarding their physiological basis. The initial phase of research development includes preclinical trials which provide evidence of key individual components and the aim is to collect data supporting safety and indicating the potential usefulness of a new drug, procedure or medical intervention. This phase is then followed by phase 0 trials which are exploratory in nature and conducted in small human samples to confirm that the intervention, in fact, produces the expected or desired results in humans before proceeding to further larger scale clinical trials.

To inform the development of a framework of factors/conditions influencing mucus transport we completed a systematic scoping review of the literature. The aim was to systematically identify literature and describe physiological factors and intrinsic conditions which facilitate airway mucus transport. The secondary aims were to 1) describe the scope of the existing research; 2) map the research development phase in which the research was conducted; and 3) describe the outcome measures used. The aforementioned information was used to identify potential research gaps and clarify the potential for conducting a meta-analysis using the available data.

The systematic scoping review was performed following the framework described by Arksey and O’Malley [12]. Before commencing this review, the Cochrane Library database was searched to ensure that no similar reviews have been published. The following databases were searched from database inception to March 2018: Medline, Scopus, Web of Science, CINAHL, Science Direct and Google Scholar (Refer to additional material for search strategies in Additional file 1: Addendum A). Papers were assessed on title, abstract and full-text level by two independent reviewers. In addition reference lists of included studies were screened independently by two reviewers. It was not necessary to contact authors requesting clarity of studies.

Papers were included if written in English, experimental (in vitro and in vivo) study designs; participants- humans over the age of 18 and animals- mammals; reported on physiological conditions investigated to optimise mucus transport or interventions/equipment to optimise mucus transport. Only papers which included the following study outcome were included: sputum volume expectorated, sputum displacement, sputum velocity, tracheal mucus clearance rate.

Papers were excluded if reporting on: mucus transport and pharmaceutical/pharmacology/pharmacodynamics; suction or subglottic secretion drainage or nasal mucociliary clearance; methods for studying mucus/mucociliary clearance models for evaluation; mucus transport in pulmonary diseased states or in systems other than the airway/respiratory system.

Data were extracted independently by two reviewers into a purposefully designed excel spreadsheet under the following headings: author, year of publication, specimen type, number of participants or model, physical factor/intervention, method of measurement, outcome measures and main findings.

The flow of information through the different phases of this review is represented in the review process flow diagram, Fig. 1 (From the PRISMA Group - [13]). The search yielded 874 papers and after the review process 35 were included in this scoping review (Refer to Fig. 1).

A brief description of the 35 papers which met the inclusion criteria can be found in Table 1. Papers were organized into pre-clinical trials and phase 0 trials.

Preclinical trials n = 31 (88%) including laboratory designs with simulated environments, in vitro - excised tracheas and cell cultures and in vivo animal laboratory interventions looking at fundamental mechanisms.

The review identified nine factors which have been investigated as influencing mucus movement. These include: temperature and humidity, bronchial perfusion, ATP, FET and cough, generation of oscillation, ventilation patterns/airflow, mucus properties, epithelial differences and positioning.

Mucus transport has been a field of research interest for more than 30 years. The review provides an overview of the factors which affect mucus transport. While there is great variability of outcome measures documented in the body of literature, all measurements reported are indicators of movement. The majority of the data is categorized as preclinical trials, the findings of which do not necessarily translate into clinical practice, however, provide evidence of fundamental elements influencing mucus transport.

We hypothesize, based on the data presented, that, in order to facilitate mucus transport, a single device will not suffice. A more holistic approach such as the development of a protocol which can include the nine factors identified in this review should be considered. We propose that factors be categorised into 1) environmental conditions and 2) patient-related conditions.

Environmental conditions identified in the review include temperature and humidity, bronchial perfusion, ATP, and epithelial differences. Exposure to temperatures below body temperature, low air humidity and diminished bronchial blood flow adversely affect mucus transport. Colder temperatures may adversely affect mucus properties and epithelial integrity. The mechanism responsible for decreased airway clearance when bronchial perfusion was stopped is unclear; however bronchial circulation may influence nutrient flow, airway wall temperature and humidity and release of mediators associated with tissue ischaemia [36]. Maintenance of airway surface liquid (ASL) volume is regulated by luminal ATP, keeping it at optimal levels of mucociliary clearance. Button et al. [14] found that in normal airway epithelia, cyclic compressive stress-induced increase in ASL ATP concentration was sufficient to induce purinoceptor-mediated increases in ASL height and mucociliary clearance.

Patient-related conditions identified in the review include FET and cough, generation of oscillation, ventilation patterns /airflow, mucus properties and positioning. A recurring finding in the literature is HFO of 13 Hz being referred to as the optimal frequency for mucus transport. Interesting to note was that HFO of chest wall was found to promote mucus clearance to a greater extent than at the airway opening. However, HFO/AO with expiratory bias enhanced clearance while inspiratory bias does not favour clearance. This data suggests that applying HFO to the chest wall or using a device to facilitate HFO at the air opening during forced expiration has the potential to facilitate mucus clearance. While higher frequencies of 25 – 68 Hz [19, 29] and hard MRCC [28] have also reported to increase mucus transport, unfortunately, these vibration and percussion frequencies are usually outside manual capability in the clinical setting.

Contrary to earlier studies investigating postural drainage positions as a technique to facilitate mucus clearance [48], the data suggests that positioning may not influence mucus transport independently [31, 39], however combined with manual physiotherapy techniques, enhances mucus transport. Tracheal orientation/gravitational effects were a confounding factor or intentionally incorporated into multiple interventions described in the sections above.

Ragavan et al. [19] found HFO in a higher tracheal inclination favoured mucus displacement and Marti et al. [28] also made use of head up position for MRCC, whereas Radford et al. [29] found the greatest increase in mucus transport with percussion in head down position. Recommendations in terms of therapeutic modalities include hard manual rib cage compressions, high-frequency oscillations and cough, all in head up 30-45°. The trachea down 5° position appeared beneficial for mucus drainage or clearance.

Peak expiratory flow or expiratory flow bias is considered a key contributor promoting mucus transport by numerous researchers in preclinical studies. Kim et al. [45] attributed increases in mucus transport to increasing airflow rates for all test solutions. Similarly, Marti and colleagues found mucus movement toward the glottis with hard MRCC corresponded with significant increases in peak expiratory flow and mean expiratory flow, with significant mean expiratory and inspiratory flow difference [28]. Both Kim et al. [17] and Volpe et al. [15] concur, emphasising the value of an increased peak expiratory flow rate (PEFR). Volpe et al. [15] identified an expiratory flow bias (PEFR>PIFR) with expiratory – inspiratory flow difference (E-I) being significant as correlated for mucus movement away from the lungs. The positive effect of expiratory flow bias on mucus clearance is also noted in combination with high-frequency airway oscillation [25, 30, 43].

It was interesting to find no evidence (Phase 0) to support controlled coughing and forced expiration as modalities to facilitate mucus transport. The mucociliary transport system includes cough clearance as a primary component. Based on the ventilation characteristics described above as promoting airway clearance, it is expected that the high flows and shearing forces generated with “huffing”/FET and coughing would affect airway clearance, however Mortensen's findings et al. [40] were contrary and Bennet's ones et al. [32] were unsustained.

King et al. [20, 46] and Zahm et al. [18] described a negative relationship between cough clearance and viscosity, viscoelasticity, spinnability and adhesivity. When investigating altering airflow patterns, Kim et al. [45] also found a decreased mucus movement with increasing viscosity of mucus. The results indicate that instructing a patient to cough will not independently facilitate the production of a sputum sample.

The results of the review must be interpreted with caution. Many of the animal trials had limitations such as those highlighted by Hooijmans et al. [49]. While it was challenging to interpret the data within a clinical context, the review highlights the complexity and multifactorial conditions needed for mucus transport. The data can now be used to develop a more comprehensive protocol to facilitate mucus transport.

The nine categories of influence identified affect the respiratory system by means of external forces or within the airway demonstrating extensive potential in terms of approaches to contributing to mucus transport. The current available level of investigations would require further development before translation into clinical practice. Due to the heterogeneity of data in terms of participants or experimental models, methodologies, measurement techniques and outcome measures used, the act of rigorous research synthesis was not undertaken. Rather an overview of existing evidence was presented, regardless of methodological quality.

Underpinning the physiology of airway mucus transport and the characteristics of interventions which facilitate airway clearance is an essential step in the process of defining populations which would most benefit from these non-surgical, non-pharmaceutical treatment strategies. This review can be used as a framework to evaluate existing physiotherapy interventions and inform future modalities in order to optimally augment airway mucus clearance.