Clinical indication for use

The general indication for mucoactive therapy is to reduce the accumulation of airway secretions, with concomitant improvement in pulmonary function and gas exchange and the prevention of repeated infection and airway damage. Diseases in which mucoactive therapy is indicated are those with hypersecretion or poor clearance of airway secretions, including cystic fibrosis (CF), acute bronchitis and chronic bronchitis (CB), pneumonia, diffuse panbronchiolitis (DPB), primary ciliary dyskinesia, asthma, and bronchiectasis. Not all patients with mucus retention benefit from mucoactive drug therapy; patients with adequately preserved expiratory airflow and cough usually have a better response. The use of mucoactive therapy to promote secretion clearance should be considered after therapy to decrease infection and inflammation and after minimizing or removing irritants to the airway, including tobacco smoke.³

Identification of agents

Table 9-1 presents general information about mucoactive agents that are approved, available, or commonly administered as inhaled aerosols in the United States. Table 9-2 presents similar information for other countries.⁴ Greater detail is given on indications, dosage and administration, hazards and side effects, and assessment of drug therapy in discussions of individual agents.

Mucoactive agents differ in their mechanism of action. Secretion properties that impair airway clearance also differ between different diseases and at different times in the course of a disease. The source and properties of airway secretions and the mechanisms of action for the mucoactive agents are the basis for clinical use of this class of drugs.

Terminology

There has been confusion regarding the nomenclature used to classify mucoactive medications. Although some authors have used “mucolytic” as a generic term for these agents, most of these medications are thought to mobilize secretions by mechanisms other than by the direct “thinning” of mucus. For example, although the mucociliary transportability of sputum may be improved by reducing sputum viscosity while preserving elasticity, the ability to clear secretions via cough seems to be greater with increased sputum viscosity and decreased adhesivity. Knowledge of mucus properties has given us tools to understand better the mechanisms of airway disease and mucoactive therapy. The currently accepted terminology is defined in the Key Terms and Definitions list at the start of this chapter. For more details on current terminology and its evolution, see Reid and Clamp,⁶ Basbaum,⁷ and King and Rubin.⁸

Surface epithelial cells

The surface of the trachea and bronchi includes primarily ciliated cells and goblet cells, at a ratio of approximately 5:1. There are more than 6000 goblet cells per square millimeter of normal airway mucosa. Goblet cells do not seem to be directly innervated in human lung, although they respond to irritants by increasing the production of mucus. Figures 9-2 and 9-3 show scanning electron micrographs of the mucus lining (Figure 9-2) and of the bronchiolar surface with the mucus stripped away (Figure 9-3). In addition to ciliated and goblet cells, microvilli, which may have a reabsorptive function, can be seen in Figure 9-3.

Submucosal mucous glands

Submucosal glands below the epithelial surface are thought to provide much of the airway surface mucin. The submucosal gland is under parasympathetic (vagal) control and responds to cholinergic stimulation by increasing the amount of mucus secreted. Evidence also suggests that submucosal glands in the respiratory tract are innervated by sympathetic axons and the peptidergic nerve system.

Two types of cells, mucous and serous, are found in the glands. Figure 9-4 shows a section of the ferret airway stained for mucin, with the surface mucous (goblet) cells and the submucosal gland serous and mucous cells identified. Secretions from the serous and mucous cells mix in the submucosal gland and are transported through a ciliated duct onto the airway lumen.

Ciliary system

Droplets of mucus from the secretory cells form plaques in the distal, nonciliated airway, and these coalesce into a continuous layer in the more proximal ciliated airway. Mucociliary transport results from the movement of the mucus gel by the beating cilia. There are approximately 200 cilia on each cell. Cilia are about 7 μm in length in larger airways and shorten to 5 μm or slightly less in smaller bronchioles. Luk and Dulfano⁹ examined the ciliary beat frequency on biopsy samples from various tracheobronchial regions and found rates of 8 to 18 Hz (Hz = 1 cycle/sec) at 37° C. A ciliary beat is composed of an effective (power) stroke and a recovery stroke with about a 1:2 ratio. In the effective stroke, the cilium moves in an upright position through a full forward arc, to contact the underside of the mucus layer and propel it forward. In the recovery stroke, the cilium swings back around to the starting point near the cell surface, to avoid pulling secretions back. Cilia beat in a coordinated or metachronal wave of motion to propel airway secretions. A functional surfactant layer lies at the tips of the cilia and separates the periciliary fluid from the mucus gel. This layer allows the cilia to transmit kinetic energy effectively to the mucus without becoming entangled. This layer also facilitates mucus spreading as a continuous layer and prevents water loss from the periciliary fluid. The properties of cilia are described in detail in an earlier review.¹⁰

Factors affecting mucociliary transport

Mucociliary transport velocity varies in the normal lung and has been estimated at about 1.5 mm/min in peripheral airways and 20 mm/min in the trachea. Transport rates are slower in the presence of the following conditions or substances, many of which are associated with airway damage:

Table 9-3 summarizes the effects of drug groups commonly used in respiratory care on ciliary beat, mucus output, and overall transport.

Food intake and mucus production

A common belief is that drinking dairy milk increases the production of mucus and congestion in the respiratory tract. Respiratory care personnel may be asked for advice on withholding milk from children with colds, respiratory infections, or chronic respiratory conditions such as CF. Pinnock et al.¹¹ inoculated 60 healthy subjects with rhinovirus-2 in a study designed to answer the following question: Does milk make mucus? Milk intake ranged from 0 to 11 glasses a day. The investigators reported no association between milk and dairy product intake and upper or lower respiratory tract symptoms of congestion or nasal secretion weight. There was a trend for cough to be “loose” with increasing intake of milk, although this was not significant. None of the subjects were allergic to cow’s milk. The investigators concluded that the data do not support the withholding of milk or the belief that milk increases respiratory tract congestion.

Structure and composition of mucus

The structure and major constituents of the mucus secreted by submucosal glands and surface goblet cells are pictured in Figure 9-5 and have been reviewed elsewhere.^5,7,12–14a Airway mucus forms a protective barrier between the respiratory tract epithelium and the environment. Mucus is composed mainly of water and ions, with approximately 5% of the content from proteins secreted by airway cells and lipids.^15–17 In health, the mucin glycoproteins are the major macromolecular component of the mucus gel. Mucins are responsible for the protective and clearance properties of mucus.^18–20

There are two major classes of mucins: the secreted and the membrane-tethered mucins.^21,22 Several secreted mucins (MUC2, MUC5AC, MUC5B, and MUC6) have genes that are clustered on chromosome 11p15 and contain domains with significant homology to the von Willebrand factor D domains that are sites for oligomerization.²³ In sputum, MUC5AC and MUC5B are the major oligomeric mucins.²⁴ MUC5AC apparently is produced primarily by the goblet cells in the tracheobronchial surface epithelium, whereas MUC5B is secreted primarily by the submucosal glands.²⁵ The membrane-tethered mucins, MUC1, MUC3, MUC4, MUC12, and MUC13, contain a transmembrane domain and a short cytoplasmic domain.²³ At least 12 mucin genes (MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7, MUC8, MUC11, MUC13, MUC15, MUC19, and MUC20) have been observed at the mRNA level in tissues of the lower respiratory tract from healthy individuals.^{21,23,26–32}

Mucus is a complex, high-molecular-weight macromolecule consisting of a mucin protein backbone to which carbohydrate (oligosaccharide) side chains are attached. At the time of this writing,²² distinct mucin proteins have been identified, but airway mucus is almost entirely composed of the MUC5AC and MUC5B secreted gel-forming mucins.²⁷ The carbohydrate content is 80% or more of the total weight of the macromolecule. This structure is similar to a bottlebrush in appearance. This general structure of protein and attached oligosaccharide side chains is termed a glycoprotein. Mucin forms a flexible, threadlike strand 200 nm to 6 μm in length³³ that is linearly cross-linked with disulfide bonds from adjacent cysteine residues. Strands may also be linked with each other by hydrogen bonding and van der Waals forces. The result is a gel that consists of a high water content (90% to 95%) organized around the structural elements and that is intensely hydrophilic and spongelike.^34,35

Under normal circumstances, bonding within mucus produces low viscosity but moderate elasticity. Although mucus incorporates water during its formation, a gel acts like both a liquid and a solid. An analogy is gelatin, which is mostly water but organizes into a semisolid by its chemical structure as the liquid gels. It is important clinically that sufficient water must be available to form mucus with normal physical properties, but once formed, mucus does not readily incorporate topically applied water.³⁶

Phospholipids are also present in the serous cell granules of the submucosal glands. When released onto the airway surface, phospholipids may serve as lubricants affecting the surface-active and adhesive properties of mucus, both of which can affect mucociliary transport function.³

In addition to the mucus gel secreted in the airway, bronchial secretions contain serum and secreted proteins, lipids, and electrolytes. Antibacterial defense in the airway is provided by mucin, secretory IgA, IgG, lysozyme, lactoferrin, defensins, and peroxidase and serine proteases. Bronchial secretions control the potentially destructive action of protease enzymes with two major antiproteases: α₁-protease inhibitor and secretory leukoprotease inhibitor (sLPI), a cationic protein found in serous secretory glandular cells.³ In healthy airways, antiproteases are present in higher quantities than protease enzymes and provide a protease screen.³⁷

Epithelial ion transport

The composition and volume of the periciliary fluid layer is regulated in part by ion transport across the epithelial cells lining the airway lumen. If the periciliary layer is not approximately the height of an extended cilium, effective mucus movement cannot occur.³⁸ Defective ion transport contributes to the cycle of retained secretions and infection seen in CF.^39,40 Normal airway epithelial ion transport is illustrated in Figure 9-6.

In the basal, unstimulated state, sodium (Na⁺) absorption into the epithelial cell is the dominant ion exchange that absorbs liquid from the airway periciliary layer. Sodium absorption occurs as an active transport process through sodium channels (epithelial sodium channel [ENaC]) on the apical (airway) side of the cell. Sodium in the epithelial cell is pumped from the cell, driven by a sodium/potassium-ATPase pump on the basolateral membrane of the epithelial cell shown in Figure 9-6. When sodium is absorbed from the airway surface liquid, there is an accompanying absorption of chloride ions and water.⁴¹ Chloride secretion can occur through at least two different types of chloride channel in the cell apex. One channel is dependent on cyclic adenosine 3′,5′-monophosphate (cAMP), the cystic fibrosis transmembrane ion conductance regulator (CFTR) channel; the other channel is calcium activated.

To summarize, under normal conditions, healthy airway epithelia can absorb salt and water driven by an active sodium transport. Normal epithelia can also secrete liquid into the periciliary fluid driven by active chloride transport through ion channels and passively through aquaporins or water channels.

Mucus in disease states

The normal clearance of airway mucus can be altered by changes in the volume, hydration, or composition of the secretion. Mucus is produced and secreted by surface goblet cells and submucosal gland cells. Water content is a function of transepithelial chloride secretion, active sodium absorption, and water transport. The composition of respiratory mucus is undergoing investigation based on structural analysis techniques.^42,43

Knowledge of these features of respiratory mucus may lead to a better understanding of diseases characterized by an abnormal production of mucus, such as CB and asthma, in which there is mucus hypersecretion, and CF, in which there is decreased intact mucin. Although it had been hypothesized that patients with CF hypersecrete viscous mucus leading to airway obstruction, it has now been shown that tenacious (but not viscous) secretions that characterize CF airway disease are composed almost entirely of DNA-rich pus.⁴⁴ Airway damage may predispose to bacterial infections in CB because of impaired clearance of mucus.

Sputum, or expectorated phlegm, is composed of mucus mixed with inflammatory cells, cellular debris, polymers of DNA and filamentous (F)-actin, and bacteria. Mucus is usually cleared by airflow and ciliary movement, and sputum is cleared by cough.⁴⁵ Purulent, green phlegm is caused by the neutrophil-derived enzyme myeloperoxidase, indicating neutrophil activation; this sputum contains very little mucin and can be considered pus.⁴⁶ Bronchial obstruction by secretions, either mucus or pus, can increase airflow resistance and lead to complete airway obstruction and atelectasis.¹² Regardless of whether the airway is full of mucus or phlegm, effective airway clearance is vital to airway hygiene.

Adhesive forces

Adhesion refers to forces between unlike molecules. In the airway, adhesive forces refer to the attractive forces between the mucus and airway surface. Adhesion severely reduces the ability to clear secretions by airflow (cough).⁶² Mucokinetic agents are either abhesives, such as surfactant, which reduces the adhesivity of secretions, or agents that increase the power of airflow and cough. Mucolytics may work, in part, by severing the bonding of mucus to the epithelium, reducing inertial (frictional) adhesion.

Cohesive forces

Cohesion refers to forces between like molecules. Cohesive forces result from the elongation of the mucus macromolecule. A property of spinnability has been described as a surrogate measure of cohesivity.

Rheology is the study of the deformation and flow of matter. The rheologic behavior of mucus describes the way it responds to forces (stress). Viscosity, or loss modulus, is the resistance of a fluid to flow. More specifically, viscosity is the proportionality constant (ratio) of applied force to rate of flow. The viscous properties of an ideal or Newtonian liquid can be described by the loss modulus, G″. Elasticity, or storage modulus, is the ability of a deformed material to return to its original shape. Ideal solids store energy during deformation, and this energy is available when the force is removed. The properties of an ideal or Hookean solid can be described by the storage modulus, G′. The complex modulus (G*) is the vectorial sum of viscosity and elasticity and is useful for describing the deformation of a pseudoplastic mucus. Figure 9-7 illustrates the concept of viscosity and of elasticity.^63–65

Mucus as a viscoelastic material

The mucus gel is a viscoelastic material and responds to an applied stress as a fluid and as a solid. As a solid, a gel has elastic deformation, storing energy with applied force, and as a liquid, a gel flows under applied force, losing (dissipating) energy. As the tips of the cilia contact the gel during the forward power stroke, the gel is stretched, and its elastic recovery causes it to snap forward. At the same time, the mucus gel flows forward as a liquid under the forward beat of the cilia.

This model of gel transport is seen in Figure 9-8, using unvulcanized rubber as an example of a viscoelastic substance. If such a rubber strip is loaded on one end with a weight and allowed to hang, it would initially stretch as an elastic solid. If the applied force remains, the strip would slowly elongate because of its viscosity (i.e., the rubber would “flow”). After removing the weight, the rubber recovers most of the elastic elongation because of stored energy, but it would not recover the entire length because of flow. Mucus behaves similarly. Mucociliary transport results from flow and forward elastic recovery. For this reason, the physical properties of viscosity and elasticity are important for efficient transport of respiratory secretions. Normal mucus generally has a relatively low viscosity, and its elasticity is high enough to provide forward propulsive energy.

Spinnability (cohesivity) of mucus

The ability of mucus to be drawn out into threads was initially identified for cervical mucus; it was termed spinnability and described in the German literature as Spinnbarkeit. It was noted that this property was essential for the motility of sperm and female reproduction. The property of spinnability was subsequently studied by Puchelle and colleagues⁶⁶ for respiratory mucus. They used a device to stretch mucus vertically at a constant rate and measured the spinnability of a mucus thread as the maximal length to which the thread could be drawn before breaking. In general, there was a significant and positive correlation between spinnability of mucus and its mucociliary transport rate. Spinnability was found to increase with increasing elasticity. Spinnability varied widely, however, with low viscosities, and mucus with high spinnability showed normal ciliary transport even though viscosity and elasticity were abnormally low. Spinnability and mucus transport were also found to decrease as the purulence of sputum from CB patients increased.

Spinnability gives information about internal cohesion forces in mucus. Cohesivity is defined as interfacial tension multiplied by the new area created after a test substance is pulled apart and can be approximated by measuring spinnability. Tenacity is defined as the product of cohesivity, and adhesive work. Tenacity is one of the strongest determinants of the ability of sputum to be cleared by cough. The greater the tenacity of sputum, the worse the cough clearability.

Non-newtonian nature of mucus

Evaluation of mucus properties is complicated by the fact that mucus exhibits non-Newtonian rheology. In an ideal Newtonian liquid, the applied force to rate of flow remains constant with changing force. A non-Newtonian substance, such as mucus, has changing viscosity (defined as the proportionality constant of force to flow) with varying applied force (shear rate). As the shear rate increases, the apparent viscosity of mucus usually decreases. Some mucus exhibits a sudden collapse of viscous behavior at high applied stress; this is called apparent yield stress. Sputum that yields may be more easily cleared by cough.⁶⁷ These changes in viscosity are consistent with rupture or change of the macromolecular chains and cross-linking network of the gel. Mucus is often thixotropic—stable at rest but becoming more fluid with applied force and then thickening again when stress is removed.

Because of its non-Newtonian behavior, evaluation of the properties of mucus and of the effect of drugs on those properties is complicated and must be performed under standardized conditions of dynamic shear rate and across the linear portion of the stress-strain curve. Otherwise, interpretation of research findings on mucus viscosity is inaccurate.^43,68 Many review articles and compendia are devoted to the physiology of mucus secretion in the lung and the nature of mucus.^{7,9,12,16,45,69–72}

Mucolysis and mucociliary clearance

Mucolytic agents decrease the elasticity and viscosity of mucus because the gel structure is broken down. Because elasticity is crucial for mucociliary transport, mucolytics have the potential for a negative effect on normal physiologic mucus clearance. Reduction of mucus gel to a more liquid state may facilitate aspiration of secretions with the use of suction catheters.⁷³ Ideally, the goal should be to facilitate physiologic clearance by optimizing the viscoelasticity of mucus. The status of mucolytic agents in pulmonary disease was well reviewed at several conferences on the scientific basis of respiratory care.^74–76

The therapeutic options for controlling mucus hypersecretion are outlined as follows:

As a mucolytic, NAC has been used in conditions associated with viscous mucus secretions. A second use of NAC is as an antioxidant antidote to reduce hepatic injury with acetaminophen overdose.⁷⁷ The drug is given orally for this use. Despite in vitro mucolytic activity and a long history of use, there are no data showing that aerosolized NAC is effective therapy for any lung disease,⁷⁸ and its use may be harmful. This harm may be due, in part, to NAC selectively depolymerizing the essential mucin polymer structure and leaving the pathologic polymers of DNA and F-actin intact. Because there are no data that show NAC to be effective for lung disease and because of the high risk of side effects, we do not recommend its use.

Dornase alfa (pulmozyme)

Peptide mucolytics, such as dornase alfa (Pulmozyme), reduce extracellular DNA and F-actin polymers. Dornase alfa is a recombinant form of the human DNase I enzyme, which digests extracellular DNA. Dornase alfa is occasionally referred to as rhDNase, for “recombinant human DNase.” In February 1994, the U.S. Food and Drug Administration (FDA) approved dornase alfa for general use in treating the abnormally tenacious DNA-containing sputum seen in CF.

Dornase alfa was the first approved mucoactive agent for the treatment of CF. Dornase alfa is safe and effective in patients with more severe pulmonary disease, defined as a forced vital capacity (FVC) less than 40% of the predicted value.⁸¹ Efficacy has not yet been shown for therapy of acute exacerbations of CF lung disease or for the treatment of other chronic airway diseases.⁸² A small phase 1 study showed no efficacy in non-CF bronchiectasis, and there was a suggestion that the use of dornase worsened disease in this adult population.⁸³ This worsening of disease may be due to the fact that secretions in COPD are composed primarily of mucin and related proteins,⁸⁴ whereas CF airway secretions include significantly less mucin and mucus, being composed almost entirely of neutrophil-derived pus.⁴⁴

Mode of action

The peptide mucolytic agent dornase alfa is similar in action to the proteolytic enzyme pancreatic dornase, which was approved for human use by inhalation in 1958 but is no longer available.⁸⁶ Dornase alfa reduces the viscosity and adhesivity of infected respiratory secretions when given by aerosol (Figure 9-9).

When mixed with purulent sputum from subjects with CF, dornase alfa reduced the viscosity and adhesivity of the sputum.⁸⁶ This reduction was associated with a decrease in the size of the DNA in the sputum. The change in sputum viscosity with the addition of dornase alfa is dose-dependent, with greater reduction occurring at higher concentrations of the drug.

Pancreatic dornase, named Dornavac by the manufacturer, the product previously removed from the market, was a bovine pancreatic DNase. This product could cause serious respiratory distress when inhaled.⁸⁷ In addition, the foreign protein could generate anti-DNase antibodies and cause allergic reactions. Differences between the human and bovine pancreatic DNase I molecules in an immunogenic region imply that some of the adverse reactions to pancreatic dornase could have been caused by an immune response. Serum antibodies to DNase were found in some patients who had been given multiple doses of bovine pancreatic DNase. Adverse effects with bovine DNase may also have been caused by the presence of contaminating proteinases, trypsin and chymotrypsin, in the drug.⁸⁶ Studies revealed no allergic response or serum anti-DNase antibodies with inhaled dornase alfa in healthy subjects or in patients with CF.⁸⁵

F-actin-depolymerizing drugs: gelsolin and thymosin β₄

Chronic inflammation is characterized by inflammatory cell necrosis and release of polymeric DNA, filamentous actin (F-actin), and intracellular enzymes from neutrophils. These inflammatory products are present in the sputum from patients with CF. DNA and F-actin in the sputum copolymerize to form a rigid network that is entangled in the mucin gel. Peptide mucolytics degrade these filaments, while leaving the glycoprotein network relatively intact. Gelsolin, an 85-kDa actin-severing peptide, has been shown to reduce the viscosity of CF sputum in a dose-dependent manner. Similarly, thymosin β₄ decreases sputum cohesivity in a dose-dependent and time-dependent manner.^90,91 Thymosin β₄ sequesters actin in CF sputum and decreases sputum cohesivity in vitro.⁹⁰ In vitro studies have shown that administration of F-actin-depolymerizing agents along with dornase alfa results in greater reduction in sputum cohesivity and viscoelasticity than administration of either agent alone.^93,94 Actin-depolymerizing agents destabilize the actin-DNA filament network and increase the depolymerizing activity of dornase alfa on the DNA filaments.

Expectorants

Bronchodilators

β agonists increase ciliary beat frequency, but this has little effect on mucus clearance. Of greater importance is that these medications can increase expiratory airflow in individuals with an asthmatic component of airway disease.¹⁰⁴ However, airway muscle relaxation can also decrease expiratory airflow by producing dynamic airway collapse in persons with “floppy airways,” such as those with airway malacia or bronchiectasis. β agonists are also mucus secretagogues and therefore can potentially increase mucus plugging if they increase dynamic collapse and decrease expiratory airflow.

Surface-active phospholipids

Surfactant is produced in the conducting airways and in the alveoli and is essential for mucociliary and cough clearance. A thin surfactant layer between the periciliary fluid and the mucus gel prevents airway dehydration, permits mucus spreading on extrusion from glands, and allows efficient ciliary coupling with mucus and, more importantly, ciliary release from mucus once kinetic energy is transmitted. With airway inflammation, surface-active phospholipids such as surfactant are often degraded by secretory phospholipases, and inflammatory peptides can inhibit surfactant function further. In the absence of surfactant, mucus sticks to the epithelium, rendering cough less effective. There is severe loss of surfactant in the inflamed airway of patients with CB or CF.^105,106

It has been reported in randomized, double-blind, placebo-controlled, multicenter studies that surfactant aerosol improves pulmonary function and sputum transportability in patients with CB or with CF and that this effect is dose-dependent. No significant side effects were attributable to the surfactant therapy.¹⁰⁷ As a wetting and spreading agent, surfactant also has the ability to increase the lower airway deposition of other aerosol medications, such as dornase alfa or gene therapy vectors, and may increase small particle translocation through the mucus layer.¹⁰⁸

Hyperosmolar saline

For many years, sputum induction produced by hyperosmolar saline inhalation has been used to obtain specimens for the diagnosis of pneumonia. Hypertonic saline has been used as an irritant to induce cough. Hypertonic saline (7%) can improve mucociliary transport and lung function, thought to be largely due to the acute effects of inducing cough and hydrating the airway surface fluid.^189,119 In a pilot study, 58 CF subjects were randomly assigned to receive 10 mL of either 0.9% normal saline or 6% hypertonic saline twice daily by ultrasonic nebulization.¹¹⁷ Spirometry was performed before treatment, at the end of 2 weeks of treatment, and 2 weeks after treatment. At the end of treatment, there was a significant increase in FEV₁ in the hypertonic saline group, with a return to baseline by 28 days. Despite pretreatment with 600 μg of inhaled salbutamol, several patients had an acute decrease in FEV₁ after inhaling hypertonic saline. Similarly, hyperosmolar dry powder mannitol improves quality of life and pulmonary function in adult subjects with non-CF bronchiectasis and significantly improves the surface adhesivity and cough clearability of expectorated sputum.¹¹⁸

Studies summarized in the Cochrane Database of Systematic Reviews confirm that the long-term use of inhaled hyperosmolar saline improves pulmonary function in patients with CF,119–121 and inhaled hyperosmolar saline or mannitol is beneficial in bronchiectasis.¹²² Although this therapy is readily available and inexpensive, it has been reported that hypertonic saline aerosol is not as effective as dornase alfa in the therapy of CF lung disease.¹²³ In CF, hyperosmolar saline promotes mucus clearance with improvement in pulmonary function and a decrease in respiratory tract exacerbations.^119,120 It is now recommended as part of the treatment regimen for this disease. However, in a study of COPD patients, there was no improvement using hypertonic saline, but cough or bronchospasm occurred more frequently than in controls.¹⁹⁰

Gravity

Gravity is not a primary mechanism for normal mucociliary transport. In health, the viscosity of the normal mucus blanket is sufficient to resist the flow of mucus into gravity-dependent terminal bronchioles. As mentioned previously, conventional CPT results in significantly greater expectoration than no treatment in patients with CF.¹³⁷ However, there is no proven benefit to adding postural drainage to CPT to patients with ineffective cough. Similarly, there is no benefit to adding postural drainage to less conventional CPT methods, such as those described subsequently.¹³⁸ Postural drainage carries a risk for patients with gastroesophageal reflux or muscle weakness.

Insufflation-exsufflation

An insufflation-exsufflation (CoughAssist) device inflates the lungs with positive pressure followed by a negative pressure to simulate a cough.¹³⁹ The cycle begins with an inspiratory pressure of 25 to 35 cm H₂O for 1 to 2 seconds, followed by an expiratory pressure of 30 to 40 cm H₂O for 1 to 2 seconds. It can be used with an oronasal mask or attached to an artificial airway. Its primary application has been in patients with neurologic muscular weakness unable to cough unassisted. Early work with COPD was suggestive of benefit, but more recent evidence is lacking in the literature.¹⁴⁰

Active cycle of breathing and forced expiratory technique maneuver

The active cycle of breathing (ACB) technique involves a combination of breathing control (relaxed diaphragmatic breathing), thoracic expansion control (deep breaths), and forced expiration from progressively increasing lung volumes. Although often used by patients with CF, there are no controlled studies documenting benefit from this mode of airway clearance beyond the forced expiratory technique (FET) manuever.¹⁴¹

FET consists of a breath taken in to mid-lung volume and air squeezed out by contracting the chest wall and abdominal muscles with the mouth and glottis kept open. The huff should not be a violent or explosive exhalation.^142,143 Exercise should be encouraged with patients, who often find that it is associated with requirements for shorter ACB sessions.

Autogenic drainage

Autogenic drainage (AD) aims to “optimize” airflow in the various generations of bronchi to move secretions without forced expirations.^144,145 This technique incorporates staged breathing starting with small tidal breaths from expiratory reserve volume, repeated until secretions “collect” in the central airways. Patients are instructed to suppress cough, and a larger volume is taken for a series of 10 to 20 breaths, followed by a series of even larger (approaching vital capacity) breaths, followed by several huff coughs. This technique requires a great deal of patient cooperation and is recommended only for patients older than 8 years of age and patients who have a good sense of their own breathing. Some uncontrolled studies have reported similar secretion clearance with AD and CPT.^141,145,146

Exercise

Exercise causes increased sputum production compared with rest.^147,148 Exercise seems to augment bronchial hygiene and should be encouraged.

Positive airway pressure

Positive airway pressure (PAP) techniques can be effective alternatives to CPT in expanding the lungs and mobilizing secretions. Evidence suggests that PAP therapy is more effective than incentive spirometry and intermittent positive pressure breathing (IPPB) in the management of postoperative atelectasis^149,150 and as an adjunct to enhance the benefits of aerosol bronchodilator delivery.^151,152 Cough, FET, and other airway clearance techniques are components of PAP therapy.¹⁵³

Pursed-lip breathing is a procedure that many patients with COPD have taught themselves to relieve air trapping caused by collapse of unstable airways during expiration. The resistance at the mouth during a pursed-lip exhalation transmits back pressure to splint the airways open, preventing compression and premature closure (similar to a fixed orifice resistor). Pursed-lip breathing represents a functional predecessor to modern device-based strategies of applying positive expiratory pressure (PEP) to the airway. Expiratory positive airway pressure (EPAP) is produced as expired air passes through a fixed orifice or threshold resistor. Continuous positive airway pressure (CPAP) is also considered a form of PAP. By preventing expiratory airway collapse, PAP increases expiratory flows and related cephalad airflow bias movement of secretions and may improve the distribution of ventilation throughout the lungs, via collateral intrabronchiolar channels.154–156

High-frequency techniques

High-frequency chest wall compression (HFCWC) has been shown to enhance secretion clearance. HFCWC can be generated by devices providing the oscillations at the airway opening or on the chest wall. These can be mechanically generated or self-generated by exhalation through an oscillatory device. High-frequency oscillations can potentially enhance mucus clearance through mechanisms, including alteration of mucus rheology, enhanced mucus-airflow interaction, and reflex mechanisms.

Shearing at the air-mucus interface could enhance tracheal mucus clearance during HFCWC.¹⁵⁷ Pilot studies suggest that dornase alfa is most effective for CF when given during HFCWC therapy than when given before or after therapy.¹⁵⁸

Oscillation of the airway

The Flutter mucus clearance device (Cardinal Health, Dublin, Ohio) combines the techniques of PEP with high-frequency oscillations at the airway opening. The weight of the ball serves as a PEP device (approximately 10 cm H₂O), and the internal shape of the bowl allows the ball to flutter, generating oscillations of about 2 to 32 Hz, varying with position of the device. The proposed mechanism of effect includes shearing of mucus from the airway wall by oscillatory action; stabilization of airways, preventing early airway closure; and facilitation of cephalad flow of mucus.

Although the Flutter has been available since about 1994, little has been published on its efficacy.¹⁵⁹ In one acute intervention study,¹⁶⁰ the amount of sputum expectorated by subjects with CF was more than three times the amount expectorated with either voluntary cough or postural drainage. Another study reported that Flutter valve therapy was an acceptable alternative to conventional CPT in hospitalized patients with CF.¹⁶¹ However, these results have not been confirmed by other studies, the relevance of expectorated sputum volume to clinical effectiveness is unproven, and most of the more recent studies of the Flutter have not shown it to be effective for airway clearance.^162–166 Device performance varies with changes in expiratory flow and angle of inclination.¹⁶⁷ This lack of efficacy under “real life” conditions may be due to the Flutter device being very tiring to use correctly resulting in poor adherence. Similar devices such as the Acapella (Smiths Medical, St. Paul, Minn.) and the Frequencer (Dymedso, Inc., Boisbriand, Quebec, Canada) may have less technique-dependent performance, but to date any improvement has yet to be reported. We generally do not recommend the use of these devices.

Intrapulmonary percussive ventilation (IPV) of the lungs involves the use of a pneumatic device called a Percussionator (Percussionaire Corp, Sandpoint, Idaho) to treat atelectasis, enhance the mobilization and clearance of retained secretions, and deliver nebulized medications to the distal airways.¹⁶⁸ With IPV, the patient breathes through a mouthpiece that delivers high-flow mini-bursts at rates exceeding 200 cycles/min. During these percussive bursts of gas into the airway, continuous airway pressure is maintained while the pulsatile percussive intraairway pressure progressively increases. Each percussive cycle is programmed by holding a thumb button for 5 to 10 seconds for the percussive inspiratory cycle and releasing the button for exhalation. Treatments of approximately 20 minutes are recommended by the manufacturer. Impaction pressures of 25 to 40 psig (pounds-force per square inch gauge) are delivered at a frequency ranging from less than 100 to 225 percussive cycles/min at 40 psig. Some small studies have reported comparable results with IPV and standard CPT.^169–171

Chest wall compression

There are several different HFCWC systems on the market, and these all are similar in operation and probably in effectiveness. These systems consist of a large-volume, variable-frequency air pulse delivery system attached to an inflatable vest that is worn by the patient so that it extends over the entire torso. Pressure pulses that fill the vest and vibrate the chest wall are controlled by the patient and applied during exhalation or throughout the respiratory cycle. Pulse frequency is adjustable from 5 to 25 Hz, with pressure varying from 28 mm Hg at 5 Hz to 39 mm Hg at 25 Hz. However, it is generally recommended, that the oscillatory frequency be held at a single frequency between 10 Hz and 15 Hz for the duration of therapy. Theoretically, vibrations to the chest cause transient increases in airflow in the lungs, to improve gas-liquid interactions and the movement of mucus. The frequency of oscillations (cycles per second) and flow bias (inspiratory versus expiratory) seem to influence effectiveness.^172,173 The vest has been reported to be effective for secretion clearance in patients with CF.^174–176 Conjecture that this device has a role in lung expansion for patients other than those with CF in the acute care setting has not been confirmed, and there are risks to using this device when patients have a weak or ineffective cough.¹⁷⁷