Respiratory Care

Mucus secretion is the first-line defense against the barrage of irritants that inhalation of approximately 500 L of air an hour brings into the lungs. The inhaled soot, dust, microbes, and gases can all damage the airway epithelium. Consequently, mucus secretion is extremely rapid, occurring in tens of milliseconds. In addition, mucus is held in cytoplasmic granules in a highly condensed state in which high concentrations of Ca²⁺ nullify the repulsive forces of the highly polyanionic mucin molecules. Upon initiation of secretion and dilution of the Ca²⁺, the repulsion forces of the mucin molecules cause many-hundred-fold swelling of the secreted mucus, to cover and protect the epithelium. Secretion is a highly regulated process, with coordination by several molecules, including soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) proteins, myristoylated alanine-rich C kinase substrate (MARCKS), and Munc proteins, to dock the mucin granules to the secretory cell membrane prior to exocytosis. Because mucus secretion appears to be such a fundamental airway homeostatic process, virtually all regulatory and inflammatory mediators and interventions that have been investigated increase secretion acutely. When given longer-term, many of these same mediators also increase mucin gene expression and mucin synthesis, and induce goblet cell hyperplasia. These responses induce (in contrast to the protective effects of acute secretion) long-term, chronic hypersecretion of airway mucus, which contributes to respiratory disease. In this case the homeostatic, protective function of airway mucus secretion is lost, and, instead, mucus hypersecretion contributes to pathophysiology of a number of severe respiratory conditions, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis.

Effective clearance of inhaled particles requires mucus production and continuous mucus transport from the lower airways to the oropharynx. Mucus production takes place mainly in the peripheral airways. Mucus transport is achieved by the action of the ciliated cells that cover the inner surface of the airways (mucociliary transport) and by expiratory airflow. The capacity for mucociliary transport is highest in the peripheral airways, whereas the capacity for airflow transport is highest in the central airways. In patients with airways disease, mucociliary transport may be impaired and airflow transport may become the most important mucus transport mechanism.

Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction in airway clearance is associated with accelerated loss of lung function in patients with obstructive lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently show clinical effectiveness.

Airway mucus hypersecretion is a feature of a number of severe respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). However, each disease has a different airway inflammatory response, with consequent, and presumably linked, mucus hypersecretory phenotype. Thus, it is possible that optimal treatment of the mucus hypersecretory element of each disease should be disease-specific. Nevertheless, mucoactive drugs are a longstanding and popular therapeutic option, and numerous compounds (eg, N-acetylcysteine, erdosteine, and ambroxol) are available for clinical use worldwide. However, rational recommendation of these drugs in guidelines for management of asthma, COPD, or CF has been hampered by lack of information from well-designed clinical trials. In addition, the mechanism of action of most of these drugs is unknown. Consequently, although it is possible to categorize them according to putative mechanisms of action, as expectorants (aid and/or induce cough), mucolytics (thin mucus), mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanisms underlying chronic mucus hypersecretion, such as glucocorticosteroids), it is likely that any beneficial effects are due to activities other than, or in addition to, effects on mucus. It is also noteworthy that the mucus factors that favor mucociliary transport (eg, thin mucus gel layer, “ideal” sol depth, and elasticity greater than viscosity) are opposite to those that favor cough effectiveness (thick mucus layer, excessive sol height, and viscosity greater than elasticity), which indicates that different mucoactive drugs would be required for treatment of mucus obstruction in proximal versus distal airways, or in patients with an impaired cough reflex. With the exception of mucoregulatory agents, whose primary action is unlikely to be directed against mucus, well-designed clinical trials are required to unequivocally determine the effectiveness, or otherwise, of expectorant, mucolytic, and mucokinetic agents in airway diseases in which mucus hypersecretion is a pathophysiological and clinical issue. It is noteworthy that, of the more complex molecules in development, it is simple inhaled hypertonic saline that is currently receiving the greatest attention as a mucus therapy, primarily in CF.

Chest physical therapy (CPT) is a widely used intervention for patients with airway diseases. The main goal is to facilitate secretion transport and thereby decrease secretion retention in the airways. Historically, conventional CPT has consisted of a combination of forced expirations (directed cough or huff), postural drainage, percussion, and/or shaking. CPT improves mucus transport, but it is not entirely clear which groups of patients benefit from which CPT modalities. In general, the patients who benefit most from CPT are those with airways disease and objective signs of secretion retention (eg, persistent rhonchi or decreased breath sounds) or subjective signs of difficulty expectorating sputum, and with progression of disease that might be due to secretion retention (eg, recurrent exacerbations, infections, or a fast decline in pulmonary function). The most effective and important part of conventional CPT is directed cough. The other components of conventional CPT add little if any benefit and should not be used routinely. Alternative airway clearance modalities (eg, high-frequency chest wall compression, vibratory positive expiratory pressure, and exercise) are not proven to be more effective than conventional CPT and usually add little benefit to conventional CPT. Only if cough and huff are insufficiently effective should other CPT modalities be considered. The choice between the CPT alternatives mainly depends on patient preference and the individual patient's response to treatment.

In health, secretions produced in the respiratory tract are cleared by mucociliary transport, cephalad airflow bias, and cough. In disease, increased secretion viscosity and volume, dyskinesia of the cilia, and ineffective cough combine to reduce secretion clearance, leading to increased risk of infection. In obstructive lung disease these conditions are further complicated by early collapse of airways, due to airway compression, which traps both gas and secretions. Techniques have been developed to optimize expiratory flow and promote airway clearance. Directed cough, forced expiratory technique, active cycle of breathing, and autogenic drainage are all more effective than placebo and comparable in therapeutic effects to postural drainage; they require no special equipment or care-provider assistance for routine use. Researchers have suggested that standard chest physical therapy with active cycle of breathing and forced expiratory technique is more effective than chest physical therapy alone. Evidence-based reviews have suggested that, though successful adoption of techniques such as autogenic drainage may require greater control and training, patients with long-term secretion management problems should be taught as many of these techniques as they can master for adoption in their therapeutic routines.

High-frequency airway clearance assist devices generate either positive or negative transrespiratory pressure excursions to produce high-frequency, small-volume oscillations in the airways. Intrapulmonary percussive ventilation creates a positive transrespiratory pressure by injecting short, rapid inspiratory flow pulses into the airway opening and relies on chest wall elastic recoil for passive exhalation. High-frequency chest wall compression generates a negative transrespiratory pressure by compressing the chest externally to cause short, rapid expiratory flow pulses, and relies on chest wall elastic recoil to return the lungs to functional residual capacity. High-frequency chest wall oscillation uses a chest cuirass to generate biphasic changes in transrespiratory pressure. In any case (positive or negative pressure pulses or both), the general idea is get air behind secretions and move them toward the larger airways, where they can be coughed up and expectorated. These techniques have become ubiquitous enough to constitute a standard of care. Yet, despite over 20 years of research, clinical evidence of efficacy for them is still lacking. Indeed, there is insufficient evidence to support the use of any single airway clearance technique, let alone judge any one of them superior. Aside from patient preference and capability, cost-effectiveness studies based on existing clinical data are necessary to determine when a given technique is most practical.