Airway clearance in patients with neuromuscular disease

Abstract

Airway clearance is a critical component of both maintenance of respiratory health and management of acute respiratory illnesses. The process of effective airway clearance begins with the recognition of secretions in the airway and culminates in expectoration or swallowing. There are multiple points on this continuum at which neuromuscular disease causes impaired airway clearance. This can result in an otherwise mild upper respiratory illness progressing unabated from an easily managed condition to a severe, life-threatening lower respiratory illness requiring intensive therapy for patient recovery. Even during periods of relative health, airway protective mechanisms can be compromised, and patients may have difficulty managing average quantities of secretions. This review summarizes airway clearance physiology and pathophysiology, mechanical and pharmacologic treatment modalities, and provides a practical approach for managing secretions in patients with neuromuscular disease. Neuromuscular disease is an umbrella term used to describe disorders that involve dysfunction of peripheral nerves, the neuromuscular junction, or skeletal muscle. Although this paper specifically reviews airway clearance pertaining to those with neuromuscular diseases (e.g., muscular dystrophy, spinal muscular atrophy, myasthenia gravis), most of its content is relevant to the management of patients with central nervous system disorders such as chronic static encephalopathy caused by trauma, metabolic or genetic abnormalities, congenital infection, or neonatal hypoxic-ischemic injury.

NORMAL AIRWAY CLEARANCE PHYSIOLOGY

Upper respiratory tract clearance

Secretions play an important role in maintaining the humidity and integrity of the upper airway epithelium. Nasal secretions are important for trapping inhaled infectious and non-infectious material. When a person is sitting or standing, oronasal secretions migrate posteriorly toward the back of the oropharynx and into the supraglottic airway. When secretions accumulate to a volume that is larger than what the supraglottic airway can accommodate, the epiglottis closes over the trachea, and secretions are cleared with a swallow.

Once secretions are sensed, normal swallowing function is required to adequately clear the upper airway. This involves a complex coordination of the oropharyngeal musculature to process the secretions into a bolus in the supraglottic airway, close the epiglottis over the trachea, and then propel the bolus towards the esophagus without allowing material to enter the larynx [1].

While there are a variety of techniques utilized by speech therapists and otorhinolaryngologists to assess swallowing, these evaluations are largely based on safe nutritive swallowing and less on clearing oropharyngeal secretions [2,3]. However, even if a patient with dysphagia has transitioned from oral to gastrostomy tube-based nutrition, the need to swallow remains critical. The average adult produces more than 500 mL of saliva per day and subconsciously swallows every one to three minutes to clear these secretions [4]. Inability to swallow will result in aspiration of a significant volume of saliva and nasal secretions, and exposure to colonizing bacteria. If this vital function is not adequately assessed and managed, it can put the patient at risk of micro-aspiration and recurrent lower respiratory tract illnesses [5]. This risk becomes greater during an acute illness when there is an increase in the volume of nasal or oral secretions.

Lower respiratory tract clearance

Mucociliary clearance

The airway surface contains ciliated and secretory epithelial cells lined by airway surface liquid. Airway surface liquid is composed of a serous fluid layer within which cilia freely beat and a mucus gel layer [6]. Mucus is a viscous and elastic gel that is produced by secretory epithelial cells (goblet cells, serous cells) and submucosal glands. It is composed of 97% water, with the remaining 3% consisting of a heterogenous collection of solids including mucins, other proteins, lipids, and cellular debris. Inhaled particles, microbes, and cellular debris are trapped in mucus and moved proximally toward the larynx by the coordinated beating of cilia [7]. Mucus is then either expectorated via a cough or swallowed. Outside of conditions of primary mucociliary dysfunction or significant bronchiectasis, it is reasonable to assume that the mucociliary mechanism or “elevator” is normal. The second method for airway clearance is a cough. Even with intact mucociliary clearance, which moves mucus from peripheral to central airways, a cough is required to expectorate it [3]. Thus, the absence of an effective cough ultimately prevents complete airway clearance.

Cough clearance

Cough clears secretions from the central airways. It occurs reflexively or voluntarily, and it can be augmented intentionally with increased depth, force, and frequency. Cough augments mucociliary clearance of secretions and debris that accumulate, or are produced, in the lower airways. The cough reflex can be stimulated by mechanical or chemical stimuli in the mainstem bronchi, carina, trachea, or larynx [8].

A cough involves four sequential events, all of which are critical. The initial event is a deep inhalation, which simultaneously places outward traction on the airways, increases the diameter of atelectatic airways, increases the elastic recoil of the lung, and lengthens expiratory muscles, thereby increasing their force-generating capability. The second and third steps (also called the compressive phase) occur congruently and involve glottic closure and forceful exhalation via near-maximal contraction of expiratory muscles, which results in a rapid increase in intrathoracic pressure that may reach upwards of 300 cm H₂O. This compressive phase lasts approximately 200 ms. In the fourth and final phase, the glottis opens and there is an expulsive flow of air up the respiratory tract. This high flow velocity creates shearing forces that dislodge mucus from the airway surface, allowing them to be propelled proximally through the respiratory tract [9–12]. Deficiency in any of these four steps will diminish cough effectiveness and thus compromise central airway clearance.

IMPAIRED AIRWAY CLEARANCE IN NEUROMUSCULAR DISEASE

There are several reasons why airway clearance can be impaired in patients with neuromuscular disease. Normal mucociliary clearance is enhanced by the variation in airway diameter that occurs during normal tidal breathing. Intrathoracic airways are compressed during normal exhalation, creating a proximal flow bias that aids in the movement of mucus by cilia. Neuromuscular weakness of the respiratory musculature may result in an inability to generate normal tidal volumes, which in turn results in smaller variations in airway diameter, chronic atelectasis, and trapping of mucus. Lower expiratory flows in patients with neuromuscular disease also result in decreased movement of secretions toward the larynx [9]. Bulbar dysfunction can lead to impaired recognition of secretions, swallowing dysfunction, and subsequent aspiration. Chronic aspiration often results in recurrent respiratory tract infections and epithelial and ciliary damage [9,12–13]. This may create a vicious cycle in which ciliary damage leads to decreased mucociliary clearance, which in turn leads to more respiratory infections and further ciliary damage.

Impaired cough is caused by several factors in patients with neuromuscular disease. Inspiratory muscle weakness interferes with the ability to generate large inspiratory volumes during the first phase of cough. Glottic closure may be compromised due to bulbar weakness, thus limiting the generation of adequate intrathoracic pressure. A similar issue arises in patients with neuromuscular disease who require a tracheostomy tube, which enters the airway distal to the larynx and is open to the environment. Finally, expiratory muscle weakness impacts both the ability to generate intrathoracic pressure during the compressive phase and expiratory flow velocity during the final phase of cough [9,12].

If untreated, impaired airway clearance leads to mucus plugging, atelectasis, and impaired gas exchange, recurrent respiratory tract infections, and eventual bronchiectasis. Pulmonary complications, many of which arise due to impaired airway clearance, are a major cause of morbidity and mortality in many types of neuromuscular disease [14–17]. Impaired airway clearance is often present well before ventilatory failure occurs and may go unnoticed and untreated, or under-treated [12]. In the setting of acute illness, aggressive airway clearance is paramount. Infection and inflammation lead to goblet cell and submucosal gland hyperplasia and hypertrophy, which in turn results in mucus hypersecretion [18]. Inflammation may damage ciliated epithelium which impairs mucociliary clearance [19]. In healthy individuals, viral upper respiratory tract infections result in decreased respiratory muscle strength that is usually of minimal clinical consequence. However, in those with neuromuscular disease and decreased baseline lung function, respiratory illnesses cause shortness of breath, decreased vital capacity, and acute hypercapnia within the first day of symptom onset [20]. The combination of increased mucus production, impaired mucociliary clearance, respiratory muscle weakness, and ineffective cough place these patients at risk for serious morbidity.

WHEN DOES A PATIENT REQUIRE AIRWAY CLEARANCE ASSISTANCE?

Several assessments can be performed to determine whether a patient with neuromuscular disease needs assistance with airway clearance. Evaluation of swallowing function is essential in determining whether the patient can adequately clear oral secretions. This may be performed using a video fluoroscopic swallow study in a patient who eats by mouth, or by clinical assessment in a patient who receives gastrostomy tube feeds.

Multiple tests exist to evaluate a patient’s cough. Maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) can be measured and are markers of inspiratory and expiratory muscle strength, both of which are critical in generating an effective cough. Peak cough flow (PCF) evaluates overall cough strength and can be measured when a patient coughs through a face mask or mouthpiece attached to a peak flow meter [12]. Cough-flow spirometry in patients with a normal cough shows cough transients or “spikes” on the expiratory flow-volume loop, which represent flow rates that are higher than maximal flows achieved during a normal forced expiratory maneuver [13]. The inability to produce cough transients is a sign of an ineffective cough and in one study of adults with neuromuscular disease was associated with increased mortality [21]. The American Thoracic Society recommends that adults with Duchenne Muscular Dystrophy who have a PCF value of less than 270 L/min or MEP of less than 60 cm H₂O when well should receive cough assistance [22]. Because pulmonary mechanics in children differ from those in adults, and similar pediatric values have not been established, caution should be used in applying these thresholds to children with neuromuscular disease [9].

PRACTICAL APPROACH TO AIRWAY CLEARANCE

When planning an airway clearance strategy, the following questions should be addressed:

1. What is being cleared?

2. Where did it come from/What caused it?

3. Where are the secretions?

4. What are the patient’s specific airway clearance limitations?

What is being cleared?

If the secretions are thin, copious, and easily mobilized, a different approach may be taken compared to thick secretions that adhere to the airways. Thin oral sections need to be discriminated from thin nasal secretions, as interventions for sialorrhea differ from that for nasal secretions. For thick secretions, it is important to determine if secretions are thick because of mucus dehydration or because of increased cellular debris. It is also important to identify whether the secretions are wholly native material or foreign aspirated material (e.g., food, formula).

Where did it come from/What caused it?

Mucosal surfaces produce mucus to help keep the mucus membranes moist and help with epithelial-based defense, while salivary glands produce saliva to hydrate the oropharynx and posterior pharynx, process, and initiate the digestion of oral intake. The volume of respiratory secretions can increase due to inflammation, either in response to irritation or an infection and before treatment it is important to determine the etiology. While treating a bacterial respiratory tract infection with thick purulent secretions is a clear management strategy, thin clear secretions can arise from a variety of different causes such as viral infection, allergic rhinitis, gastroesophageal reflux (with or without aspiration) or airborne irritants such as smoke.

If excessive clear, thin secretions are present in the oropharynx, larynx, and/or trachea, and the patient is not acutely ill, then decreased clearance of secretions should be considered as an underlying cause. In this scenario, which typically occurs in patients with dysphagia who are not fed orally, the patient either does not recognize the presence of secretions or does not adequately clear them. Patients with inadequate swallowing capacity or an absent gag reflex are at serious risk for aspiration and require frequent oral suctioning and cough-assistance maneuvers.

Where are the secretions?

This is related to the previous question, but it is important to consider separately. With a viral respiratory tract illness, secretions may be increased throughout the entire respiratory tract or only in one segment among the bronchi, trachea, oral, or nasal airway. The first approach should always be to increase the frequency of upper and central airway clearance with suctioning, but there are certainly times when that is not possible and augmenting airway clearance with mucus mobilization techniques become necessary. The use of pharmacologic interventions can help reduce secretion production, improve secretion consistency, and/or dilate airways to enhance secretion clearance. The pharmacologic approach is dependent both on the character of secretions and their location, and knowledge of both is necessary to design an optimal treatment plan.

What are the patient’s airway clearance limitations?

While it is not possible to completely correct abnormal airway clearance either with additional physiotherapy or pharmacotherapy, it is certainly feasible to support a patient’s airway clearance limitations to keep the patient healthy with a manageable amount of care. Doing so starts with a clear understanding of what the patient’s limitations are and then designing a plan to support them. If the patient does not have the neuromuscular capacity to produce an effective cough or the ability to do so on demand or when needed, then providing cough augmentation is a critical first step.

SPECIFIC THERAPIES

There are two general components of airway clearance: mucus mobilization and airway clearance [10]. While complementary, they need to be considered separately. As an example, patients with cystic fibrosis have an effective cough but because airway mucus is dehydrated and tenacious, mucus mobilization with mucolytic therapy is extremely important to move secretions into central airways where they can be expectorated by the patient. However, a patient with an ineffective cough due to neuromuscular weakness who has thin peripheral secretions requires assistance clearing the central airways with cough augmentation such as mechanical in/exsufflation (MIE) [23]. An overview of mucus mobilization and airway clearance therapies is provided in Table 1.

Table 1.

Overview of mechanical and pharmacologic airway clearance therapies.

Airway clearance	Description	Use	Proposed mechanism of action	Advantages	Disadvantages
Mechanical in/exsufflation	Positive and negative pressure insufflation administered through a facemask or airway, simulating natural cough	Use for patients with ineffective cough	Increases peak cough flow, shearing mucus from central airways	Does not require patient effort	– Expensive – Rare adverse events include barotrauma, upper airway collapse, arrhythmia, GERD
Mucus mobilization
HFCWO	Air rapidly injected in and out of hoses attached to an inflatable vest, producing rapid chest wall compressions	Use for patients with recurrent infections, bronchiectasis, or thick secretions that are difficult to mobilize	– Shear forces mobilize mucus from peripheral airways – Facilitates movement of secretions toward the larynx – Decreases mucus viscosity	Does not require patient effort	– Expensive – May be difficult to obtain due to limited experience in NMD – Must be followed by central airway clearance (e.g. MIE, suctioning) to avoid airway obstruction
IPV	Bursts of air at high frequencies, constant distending pressure through a facemask, mouthpiece, or airway	Use for patients with recurrent respiratory infections, bronchiectasis, thick secretions, or atelectasis	– Airway walls vibrate, loosening secretions – Dilates airways through distending pressure – Fills distal lung units with fresh gas	Can deliver medications simultaneously	– Expensive – Difficult to obtain for home use – Must be followed by central airway clearance (e.g. MIE, suctioning) to avoid airway obstruction
Chest percussion	Using a cupped hand or facemask to percuss the chest wall	Use in any patient that needs assistance to mobilize secretions from peripheral airways	Mobilizes secretions from peripheral airways	No cost	– Time-consuming – Caregiver fatigue
Hypertonic saline	Inhaled 3% or 7% sodium chloride	Use for patients with thick, dehydrated secretions	1. Increases depth of airway surface liquid 2. Mucolytic properties 3. Triggers cough 4. Anti-biofilm properties	Inexpensive and widely available	– Mucorrhea in hyper secretors – Bronchospasm
Beta-2 agonists	Albuterol	Use for patients with bronchospasm or to dilate airways for airway clearance	– Dilates airways for secretion clearance – Increases ciliary beat frequency	Inexpensive and widely available	– May increase mucus production – Side effects include tachycardia, tremor – May worsen airway obstruction in patients with tracheobronchomalacia
Dornase alpha	Inhaled recombinant human DNase	Consider trialing in patients with thick, purulent secretions	Cleaves DNA which frees proteins which are then broken down by proteolytic enzymes, reducing mucus viscosity		– No evidence for its use chronically in NMD
Anticholinergic medications	Glycopyrrolate, inhaled ipratropium, sublingual atropine, scopolamine patch	– Use to decrease oral/airway secretion volume  – Ipratropium may be used for bronchodilation	Block muscarinic receptors, reducing secretion production and relaxing airway smooth muscle		– Risk of mucus plugging by thickening secretions – Anticholinergic side effects include urinary retention, constipation, dry mouth, CNS side effects
Nasal secretion therapies	Oxymetazoline Nasal ipratropium Antihistamines Nasal corticosteroids	Use for patients with copious nasal secretions or nasal congestion		Helpful in patients with copious nasal secretions
Salivary gland injection	Botulinum toxin A or B	Use for severe sialorrhea refractory to medical therapy	Inhibits acetylcholine release from presynaptic neurons, preventing cholinergic activity	Effective, may reduce medication burden	– Requires repeat injections roughly every 3 months – Invasive

SPECIFIC THERAPIES: MUCUS MOBILIZATION

The goal of mucus mobilization is to enhance the movement of secretions from peripheral to central airways where they can then be coughed out or suctioned. While this is normally achieved by the mucociliary escalator, patients with ciliary dysfunction caused by recurrent respiratory infections or a large volume of secretions that overwhelms the mucociliary escalator may benefit from assistance with mucus mobilization. This can be achieved either (1) mechanically by freeing mucus from the airway wall or (2) pharmacologically by decreasing mucus viscosity or volume. All mucus mobilization maneuvers must be followed by a mechanism to clear the central airways, either with cough augmentation or deep suctioning. Failure to do so not only render mucus mobilization ineffective but may be dangerous for the patient by causing acute obstruction of the central airways by mucus that has been mobilized from peripheral airways.

Mechanical mucus mobilization

Chest percussion

Chest percussion is a common mucus mobilization technique that can easily be performed by a caregiver. It involves using a cupped hand, padded cup, or facemask to percuss the anterior and posterior chest wall to mobilize mucus. While there is limited data regarding its effectiveness in neuromuscular disease [24], it is commonly used because it can be easily performed by caregivers, does not require patient participation, and has no associated cost. During acute illness when frequent mucus mobilization is required, chest percussion may become difficult to perform adequately due to caregiver fatigue.

Intrapulmonary percussive ventilation

Intrapulmonary percussive ventilation (IPV) provides bursts of air at high frequencies (60 to 400 cycles/min) superimposed on the patient’s respiratory pattern through a facemask, mouthpiece, or artificial airway. Additionally, a constant distending pressure between 10 and 40 cm H₂O is delivered. The high-frequency bursts cause the airway walls to vibrate, which in turn loosens secretions. The airways are dilated by the constant distending pressure, and distal lung units beyond secretion-filled airways can be aerated. In one study, measured expiratory flows exceeded inspiratory flows with the IPV device, which enhances airway clearance [25]. Medications, such as bronchodilators, can be administered simultaneously through the delivery interface to further dilate the airways [9,14,22]. In one randomized study of adolescents with neuromuscular disease, IPV was superior to incentive spirometry in reducing the need for antibiotics [26]. Toussaint et al. studied a small group of patients with DMD and tracheostomy tubes who produced significant volumes of mucus daily. They found that IPV was safe and enhanced the clearance of secretions [27]. In a small retrospective cohort study of 8 children with global developmental delay and tracheostomy, the use of IPV compared to high-frequency chest-wall oscillation (HFCWO) was associated with decreased respiratory illnesses, hospitalizations, and use of bronchodilators and steroids [28]. One case series of 3 patients with neuromuscular disease and persistent pulmonary consolidation reports that 2 of the patients had a dramatic improvement in physical exam, hypoxemia, and radiographic abnormalities with the initiation of IPV. This same study notes that the third patient, a 16-year-old boy with DMD and cardiomyopathy, developed acute hypoxemia and complete heart block after treatment with IPV, apparently related to acute airway obstruction from mobilized secretions. Symptoms resolved with manually assisted cough and suctioning [29]. This reinforces the necessity of following mucus mobilization with airway clearance therapy, as noted above. One important point regarding IPV is that drug delivery may be unreliable compared to a standard jet nebulizer [30].

High-frequency chest-wall oscillation

HFCWO is a mucus mobilization technique that is accomplished by wearing a vest that is attached to an air pulse generator. Air is rapidly injected into and withdrawn from hoses that attach the vest to the machine, which produces rapid chest compressions at specific frequencies (usually between 5 and 20 Hz) and pressures. This produces shear forces at the air-mucus interface, mobilizing mucus from peripheral airways. Additionally, HFCWO is proposed to generate higher expiratory than inspiratory flows, which facilitates the movement of secretions proximally [31]. Finally, there is evidence that mucus viscosity is reduced by HFCWO [9,32]. While there are no large prospective studies regarding the use of HFCWO in neuromuscular disease, several small studies suggest that it may be beneficial. Fitzgerald et al. prospectively studied 22 children with neurologic impairment and frequent respiratory-related hospitalizations before and after initiation of HFCWO and found that HFCWO was associated with fewer hospitalizations in the first and second years of its use [33]. In a randomized trial of 23 children with either cerebral palsy or neuromuscular disease comparing HFCWO with standard chest physiotherapy, adherence was significantly better and there was a trend towards decreased hospitalizations requiring intravenous antibiotics in the HFCWO group. Lange et al. randomized 35 patients with ALS to receive HFCWO or standard care for 3 months. Those who received HFCWO considered the treatment to be helpful and had a significant decrease in breathlessness, fatigue, and “noisy breathing” compared to the control group. In patients with impaired forced vital capacity (FVC) at study initiation, the HFCWO group experienced a significantly slower decline in FVC compared to the control group [34]. In a study of a healthcare claims database including 426 patients with neuromuscular disease who started using HFCWO, its use was associated with decreased medical costs, hospitalizations, and pneumonia [35]. HFCWO is usually well-tolerated, and in nearly all of the above-cited studies, there were no therapy-related adverse events. Because HFCWO does not clear secretions from central airways, it is important to follow treatment with an airway clearance technique. This is highlighted by a case report that details an episode of acute hypoxemic respiratory failure that developed in an 11-year-old child following HFCWO treatment, thought to be caused by aspiration of mobilized secretions [36].

Pharmacologic mucus mobilization

Several pharmacologic agents may be used for mucus mobilization in patients with neuromuscular disease by decreasing mucus viscosity, which improves mucociliary clearance [7]. Given a lack of clinical trials in patients with neuromuscular disease, the use of most pharmacologic agents is considered off-label [9].

Inhaled hypertonic (3% or 7%) saline may aid in mucus clearance by several different mechanisms. It appears to have a mucolytic effect in two ways. Firstly, it disrupts ionic bonds within mucus gel and reduces cross-linking, which decreases mucus viscosity [37]. Furthermore, it may dissociate leukocyte DNA from mucoproteins, which then facilitates the breakdown of protein by proteolytic enzymes [38]. Hypertonic saline also increases the depth of airway surface liquid via an osmotic effect [39], which likely improves mucociliary clearance and more effectively triggers the cough reflex [40]. Additionally, one in vitro study found that exposure of Pseudomonas aeruginosa to 6% saline resulted in altered biofilm formation and reduced virulence factor production [37]. Therefore, it would seem, at least in theory, that hypertonic saline would be useful in enhancing mucociliary clearance in patients with thick secretions.

However, hypertonic saline has mostly been studied in conditions with mucociliary abnormalities, such as cystic fibrosis, and not in neuromuscular disease. Therefore, it should be used judiciously for a specific, defined indication. For example, if a patient develops an acute respiratory illness resulting in thick secretions that are difficult to clear, inhaled hypertonic saline may be useful to facilitate the clearance of those secretions. However, when the illness resolves and the patient’s secretions are no longer thick, there would be no further need for it. Because hypertonic saline non-selectively hydrates thick, thin, and normal mucus, it increases mucus volume [41] which may be deleterious in patients with impaired airway clearance capabilities. Furthermore, Bennett et al. found that in healthy human subjects, mucociliary clearance (as measured by clearance of radiotracers) slowed several hours after an initial acceleration when aerosolized hypertonic saline was administered [42].

Dornase-alpha (recombinant human DNase, rhDNase) is a mucolytic medication that reduces the viscosity of cystic fibrosis (CF) sputum via depolymerization of extracellular neutrophilic DNA, allowing natural proteolytic enzymes to degrade mucus proteins [43]. When used in patients with cystic fibrosis, rhDNase improves lung function and decreases pulmonary exacerbations [44]. However, in a randomized control trial in adults with non-CF bronchiectasis, regular use of rhDNase for 24 weeks was associated with an increased risk of exacerbations and worse lung function compared to placebo [45]. Therefore, routine use of this medication is recommended in cystic fibrosis patients but not in individuals with non-CF bronchiectasis [46,47]. Clearly, caution is advised before applying treatments to populations with differing pathophysiology. rhDNase has not been studied in patients with neuromuscular disease; therefore, it should not be routinely used [48]. However, in a patient with purulent secretions who is not responding to other therapies, a trial of rhDNase may be considered with appropriately defined endpoints.

N-acetylcysteine (NAC) exhibits mucolytic properties by cleaving disulfide bonds in mucus [49]. Its efficacy is questionable in respiratory disease in general [50] and it has not been studied in patients with neuromuscular disease. The aerosolized form may be poorly tolerated due to its propensity to cause bronchospasm and its sulfurous odor [50].

Beta-2 agonists (e.g., albuterol) are primarily used as bronchodilator medications, although they have also been demonstrated in-vitro to increase ciliary beat frequency [51,52], and possibly enhance short-term mucociliary clearance in healthy human subjects and those with asthma and chronic bronchitis [53]. Furthermore, they may reverse neutrophil elastase-induced depressed mucociliary clearance [54]. However, they also directly stimulate secretion production via airway adrenergic receptor stimulation [18], and may cause peripheral airway secretory cell hyperplasia [55]. Because higher doses may be required to achieve the enhanced mucociliary clearance effect [18], which in turn would increase side effects (mucus production, tachycardia, tremors), beta-2 agonists should not routinely be administered solely to enhance mucociliary clearance. There are limited data available to inform if and how beta-2 agonists should be used in patients with neuromuscular disease. They are often prescribed to dilate the airways before an airway clearance treatment or to prevent bronchospasm that could be caused by an alternative medication such as inhaled hypertonic saline. As there is no data to support their use in neuromuscular disease, careful attention should be paid by the prescriber to whether these medications are beneficial to the patient. In patients with concomitant tracheobronchomalacia, beta-2 agonists may exacerbate airway obstruction due to the relaxation of airway smooth muscle [56].

Specific therapies: airway clearance

Mechanical in-exsufflation

Mechanical in-exsufflation (MIE) devices have been central to airway clearance in patients with respiratory muscle weakness [23,57] and are widely used in the less defined group of patients with static encephalopathy and an inability to cough on demand. MIE therapy involves the administration of positive pressure insufflation, allowing the lungs to passively and deeply expand, followed by rapid negative pressure exsufflation. This produces a high expiratory flow velocity that mimics a cough, which shears secretions from the walls of the central airways and moves them proximally toward the mouth where they can be expectorated or suctioned [9]. These pressures can be administered either via a facemask or an artificial airway. Customizable settings include positive pressure, negative pressure, inspiratory and expiratory pause times, and inspiratory flow rate. Prescribing effective MIE requires a careful assessment of the pressures needed for full inspiration and then for a complete exhalation, and settings must be individualized for each patient. In a lung model study, longer insufflation times yielded increased exsufflation flows, and a PCF greater than 2.7 L/s was only generated using in/exsufflation pressures of at least +/−30 cm H₂O [58].

Because the maneuver involves relatively high pressures to augment inhalation and exhalation, patients may experience some discomfort when starting to use MIE. Several aspects of the MIE treatment need to be considered when introducing the device: (1) increased expansion of the rib cage, (2) the patient tolerating substantial positive pressure at the mouth, (3) tolerating negative pressure augmenting exhalation, and (4) the resulting transmural pressure gradient favoring pharyngeal narrowing. Once the patient can accommodate these maneuvers, and the caregiver can deliver the treatment in a way that works for the patient, the pressures can be gradually increased into a more patient-specific “therapeutic” range. This aspect of the process is very often purely qualitative and best performed by an experienced physiotherapist. This second stage is critical since applying pressure on inspiration and exhalation that does not meaningfully increase the depth of inspiration and exhalation will not provide therapeutic benefit.

The next component of MIE therapy is determining when to use it. In an ideal world, MIE would be used “whenever a cough is needed.” However, this is both challenging for a patient to identify and even more difficult for caregivers to accommodate. When a patient is well, only a small volume of mucus may be produced that should be easily moved up the respiratory tract by the mucociliary elevator and then expectorated with a modest cough or removed with suctioning. Even though it is typically recommended to perform MIE treatments twice daily, when a patient is at their relative baseline status [10,11,23,57], some patients choose to not do so and remain well.

The most critical part of an effective MIE treatment strategy is increasing its use as soon as the need arises (i.e., increasing secretion production) [10,11], which happens semi-autonomously in patients who have an intact cough. However, without an effective cough, an otherwise mild illness may progress to a lower respiratory tract illness and acute respiratory failure. In addition, it is critical to have the latitude and the recognition of the need to increase the number of in/exsufflation cycles per treatment and/or the frequency of treatments needed to clear the airways. In/exsufflation pressures may need to be increased in situations where pulmonary mechanics are altered, such as in acute illness [58].

Evidence regarding the efficacy of MIE in neuromuscular disease is provided by several small studies. Compared with other cough augmentation techniques, the use of MIE results in a greater increase in PCF [59]. In one study of 11 patients with neuromuscular disease admitted to the intensive care unit (ICU) for a respiratory infection, intubation and cricothyroid mini-tracheostomy rates were decreased in those who received MIE compared to historical controls [60]. Miske et al. found MIE to be safe, well-tolerated, and effective in a retrospective cohort study of 62 patients with neuromuscular disease, although the studied outcomes were too rare to permit meaningful conclusions [61]. In survey studies of families of children with neuromuscular disease, MIE was perceived to be well-tolerated and effective, and provided a useful tool to manage respiratory illness at home [62,63]. A 2013 Cochrane review found insufficient evidence for or against the use of MIE in patients with neuromuscular disease due to the paucity of high-quality studies [64]. However, an American Thoracic Society consensus statement “strongly supports the use of MIE in patients with Duchenne Muscular Dystrophy and also recommends further studies of this modality.” [22].

Reported adverse events related to the use of MIE include barotrauma, cardiac arrhythmias, worsening of gastroesophageal reflux disease, hemoptysis, and abdominal distension. While these have been reported (mostly in adults), they are rare [9,24]. In a study of patients with ALS and bulbar dysfunction, Andersen et al. found severe upper airway obstruction that occurred due to the adduction of laryngeal structures during MIE which limited the effect of MIE, and that customizing settings (e.g., increasing inspiratory times) may help overcome this limitation [65].

Though there is consensus that the ideal approach to airway clearance is MIE [10,11,23,57], there are some who prefer, and effectively use, just mechanical insufflation, intermittent positive pressure breaths (IPPB), or non-mechanical physiotherapy techniques including manual breath stacking followed by a mechanically assisted cough [66,67]. Whatever the approach used for airway clearance, it is important that is it performed as the final step of a treatment regimen after any adjunctive treatments to mobilize mucus, such as mucolytic therapy and physiotherapy techniques.

OTHER PHARMACOTHERAPIES

Before considering using pharmacotherapies to help with upper airway secretions, it is important to be clear on what abnormality is present and what the treatment is targeting. As an example, in someone with excessive saliva, it should be determined if it is due to true hypersalivation or inadequate swallowing and clearance. Because of the challenge in finding the proper therapeutic window with the use of anticholinergic medications, it is important to first address swallowing dysfunction, perhaps by integrating a speech and swallowing therapist, to improve swallowing.

Another consideration is defining “excessive” secretions. This will in part be related to that patient’s ability to cough and clear secretions when they accumulate to a point where aspiration is a risk. The other issue is the feasibility of the care, specifically upper airway suctioning, needed to keep the patient safe. This involves looking at each patient as an individual and setting the goal of “adequate” upper airway secretion clearance, understanding that achieving “perfection” regarding upper airway secretions is often not possible.

Anticholinergic medications

Cholinergic nerves, by way of the neurotransmitter acetylcholine, provide the predominant neural control pathway for mucus secretion in the airways. Several different muscarinic receptors play a role in secretion production. M₃ receptors directly mediate mucus and water secretion, M₁ is involved mainly in water secretion, and the M₂ receptor provides negative feedback to inhibit further acetylcholine release [68]. Anticholinergic medications work by blocking muscarinic receptors, thereby decreasing mucus and/or water secretion. They also relax airway smooth muscle, providing a bronchodilator effect. While inhaled anticholinergic medications such as ipratropium bromide (short-acting) and tiotropium bromide (long-acting) are commonly used in chronic obstructive pulmonary disease (COPD) to improve lung function and decrease mucus production [18,69], they have not been studied in patients with neuromuscular disease.

Treatment of sialorrhea

Sialorrhea is a major concern in patients with neuromuscular disease, either due to increased production or decreased clearance of oral secretions. Because of swallow dysfunction, these secretions may be aspirated into the airway, causing respiratory morbidity. Glycopyrrolate is an anticholinergic medication available in liquid form that is used to treat sialorrhea in individuals with underlying neurologic disorders. In children with cerebral palsy or other neurodevelopmental disorders, oral glycopyrrolate is effective in reducing chronic drooling. Anticholinergic side effects such as constipation, dry mouth, and urinary retention are relatively common. Thick secretions may also occur, requiring careful dose titration to achieve the appropriate balance between decreased volume but manageable consistency of secretions [70]. Because glycopyrrolate is a quaternary amine and does not cross the blood–brain barrier, central nervous system (CNS) toxicity is limited [71]. Sublingual atropine and scopolamine patches may also be used to treat sialorrhea, although because they cross the blood–brain barrier, CNS side effects may limit their use [72]. Medication is successful in up to two-thirds of patients in managing sialorrhea [72]. For those who fail to respond to medication, salivary gland botulinum toxin injection may be effective in reducing oral secretions by inhibiting the presynaptic release of acetylcholine, which in turn decreases cholinergic production of secretions. However, the effect is transient and repeat injections are required. In one review of long-term outcomes of 65 patients with ALS and Parkinson’s Disease treated with botulinum toxin injections for the management of sialorrhea, a benefit was seen in 89% of patients for a mean duration of approximately 3 months [73]. Salivary gland surgery for sialorrhea may be considered if other treatment options fail [72].

Gastroesophageal reflux

Gastroesophageal reflux is common in patients with neuromuscular disease [74,75] and can also increase upper airway secretions both physically, during regurgitation, and topically with acidic irritation of the mucus membranes of the oropharynx and posterior pharynx. Although it may be difficult to assess the contribution of reflux to increased secretions, empiric treatment with antiacid and/or prokinetic therapy and assessment of effect may be useful in an individual with neuromuscular disease and copious oropharyngeal secretions.

Treatment of nasal secretions

Nasal secretions may be significant depending on whether the patient has an underlying condition that causes nasal congestion such as allergic rhinitis or is experiencing episodic mucosal inflammation due to a viral infection. Although not studied specifically in neuromuscular disease, treatment with an antihistamine or intranasal corticosteroid (for allergic rhinitis), topical adrenergic agonist such as oxymetazoline (decongestant), or topical anticholinergic such as nasal ipratropium may be helpful. Nasal suctioning should be approached with caution due to the increased risk of bleeding and subsequent potential airway compromise.

CONCLUSION

Patients with neuromuscular disease can have a variety of different types of respiratory dysfunction that often lead to significant airway clearance abnormalities throughout the respiratory tract. Acknowledging this, it is important to consider a wide range of treatment strategies and customize the approach for each patient to treat their specific dysfunction. In addition, it is particularly critical to approach support of airway clearance dynamically as it may change in a patient based on their clinical status.

Educational aims.

The reader will be able to:

• Understand the normal physiology of upper and lower respiratory tract secretion clearance mechanisms and how they are impaired in patients with neuromuscular disease.

• Recognize the indications for utilizing different mechanical and pharmacologic therapies to assist with mucus mobilization and airway clearance.

• Develop a thoughtful and patient-specific treatment approach for managing airway clearance.

• Identify the limitations and adverse effects of specific airway clearance therapies.