Understanding the respiratory system is an essential part of critical care. Readily available, concise sources summarizing key components of respiratory defence in animals are lacking. In this lecture we will explore three components of respiratory defence and consider their roles in critically ill patients. Respiratory immunology is a complex and exhaustive field, which will not be covered in this lecture.

The learning objectives of this lecture are:

• To discuss the cough reflex for airway clearance.
• To explore the connection between breathing and swallowing.
• To explain the two major pathological mechanisms of mucociliary escalator dysfunction.

Protective Reflexes

1. Coughing

Coughing is the forced expulsion of air against a closed glottis. Involuntary coughing, i.e., a reflex, is recognized in dogs and cats. Voluntary coughing occurs in people. Coughing is a protective reflex assisting in airway clearance of exogenous (e.g., foreign material, pathogens) and endogenous (i.e., excessive secretions) material. Its effect is additive to other systems, such as the mucociliary escalator. Coughing as a defence mechanism is considered purposeful; however, coughing can also be a warning feature of an underlying disease or a nuisance when the reflex is triggered without a purpose for defence. Aberration of the cough reflex results in either hyper- or hypo-activation, the latter being vitally important in critical care.

Three phases are recognized. During the inspiratory phase, there is a large intake of air to prime the system. The volume of air taken in is important, as insufficient volume results in an unproductive cough. During the compressive phase, thoracic pressure is rapidly increased by compressing the intrathoracic air against a closed glottis. The diaphragm, thoracic wall and the abdominal muscles generate this compressive pressure, whilst the aryepiglottic muscles, oblique arytenoid muscles, thyroepiglottic muscle work to keep the epiglottis closed. During the expulsive phase, the epiglottis is rapidly opened, and air is forcefully expelled, leading to characteristic sounds. Coughing can occur as a singular event or can continue several times. Airway clearance can be achieved after a single cough, a bout of coughing or continued coughing after an obvious foreign body has been expectorated does not necessarily indicate persistence of foreign material. If the trigger does persist—for example excessive secretions—coughing is expected to continue. Attenuation of, or failure to cough, is potentially problematic.² Humans can reportedly cough at 500 miles per hour (800 Km/h).

Sensory vagal fibres form the afferent pathway. Coughing is due to interactions between the respiratory centres (dorsal medullary group, ventral medullary group and the pontine medullary group), rather than a specific “cough centre.” The respiratory centres have been summarized elsewhere. Efferent signals travel via the vagus, phrenic and spinal motor nerves to the effector organs, i.e., diaphragm, intercostal muscles and pharynx.

Cough receptors of various types are present within the trachea, large and small airways. Extra-respiratory, mechanical receptors also appear to be present in auditory canals, ear drums, nasal sinuses, pharynx, pleura, pericardium and diaphragm. Stimuli for these receptors include mechanical forces (stretch, pressure), chemicals (bradykinin, capsaicin) and inflammatory mediators (PGE₂, histamine). Rapidly adapting and slowly adapting stretch receptors are primarily mechanically stimulated, whereas pulmonary and bronchial C-fibres are stimulated by chemicals. Slowly adapting stretch receptors are important for the Herring-Breuer reflex, preventing harmful overdistension. C-fibre activation can result in bronchoconstriction, increased airway secretions, bradycardia and hypotension.¹ These receptors input to the respiratory centres via the vagal nerve.

Hyper-active aberration of the cough reflex often presents as chronic coughing. Chronic coughing is daily, unnecessary (nuisance) coughing, lasting >8 weeks. A refractory cough fails to respond to intervention, whereas an unexplained cough is where the clinician fails to identify the cause. Unnecessary coughing is important to the critical care practitioner, as it causes airway mucosal damage and compromise of the respiratory defences. Forceful coughing can plausibly result in injury to the respiratory system or haemodynamic compromise in susceptible patients due to large swings in volumes and pressures. Rib fractures are reported in cats with respiratory disease. Hypo-active aberration of the cough reflex is perhaps more important, though veterinary literature seems to be lacking. In aging humans, degradation of the sensory (afferent) pathways of the cough reflex has been identified. Failure of the cough reflex is associated with aspiration pneumonia, whereas failure of the swallowing reflex alone is less consistently associated with aspiration pneumonia. I have seen a similar scenario in a dog recovering from tetanus: she was able to swallow, though developed aspiration pneumonia, perhaps due to failure to cough. Much of the human literature on hypo-active aberration of the cough reflex has been conducted in dementia patients, so caution is necessary when extrapolating into veterinary species. Opioids are frequently used in veterinary critical care patients: they can depress the cough reflex and are used as antitussives.

Angiotensin-converting enzyme inhibitors (ACEIs) can increase coughing in humans and guinea pigs. A literature search did not find evidence to support ACEI-induced coughing in dogs and cats. The association, if any, between ACEIs and coughing in critically ill dogs and cats, specifically those with cardiac disease, is unknown.

2. Swallowing

Swallowing, or deglutition, is a complex process involving >30 muscles and nerves. In veterinary medicine, swallowing disorders (dysphagia) tend into the realm of internal medicine. However, in critically ill humans, swallowing disorders are being increasingly recognized. Dysphagia is associated with increased risk for aspiration pneumonia and negatively affects nutrition, quality of life, morbidity and mortality in humans.

This lecture will predominantly consider oropharyngeal dysphagia.

Swallowing occurs in four phases: oral preparatory, oral transit, pharyngeal and oesophageal. The oral phases are under voluntary control. Mastication, lubrication and bolus formation (shaping for swallowing) occur during the first phase. The bolus is then transited caudally to the oropharynx. Cranial nerves V and VII innervate the lips and cheeks, cranial nerve XII innervates the tongue. Pathologies of these nerves can affect the oral phases. Phase three is involuntary, i.e., a reflex. Arrival of the bolus in the oropharynx triggers the reflex: the soft palate is elevated, preventing inappropriate entry into the nasopharynx; the larynx and hyoid are elevated and moved rostrally; the epiglottis retroflexes and the vocal folds close to seal the larynx. Laryngeal elevation assists in opening the upper oesophageal sphincter. Coordination between pharyngeal constriction, laryngeal closure and opening of the upper oesophageal sphincter is essential for normal passage of the food bolus. Swallowing apnoea, the essential temporary cessation of respiration during swallowing, occurs during phase three. Dyssynchrony between laryngeal closure, apnoea and opening of the upper oesophageal sphincter has been described in critically ill humans. Phase four is involuntary: the bolus transits through the oesophagus. Primary peristaltic waves are induced by swallowing, whereas secondary waves are induced by the presence of the bolus. Awake humans swallow at least once per minute at rest and >5 times per minute whilst eating; whilst sleeping, swallowing is decreased to once every 5–10 minutes. The swallowing centre in the medulla oblongata receives sensory input via cranial nerves V, IX, X. Information is integrated with impulses from various peripheral and central regions and motor responses are initiated. Swallowing and respiration are highly coordinated. The timing of swallowing in the respiratory cycle and the timing of swallowing apnoea in relation to inspiration or expiration, may be altered in humans with dysphagia and hypercapnia, and may be associated with aspiration in patients with Parkinson’s disease. The normal sequence seems to be expiration, apnoeic pause, followed be continued expiration: the continuation of expiration might serve to protect the airway. Different breathing-swallowing patterns may be associated with an increased risk of aspiration related disorders. Critically ill humans with respiratory distress seem to have a shortened swallowing apnoea period. How this translates into veterinary medicine is unclear: a recent review discusses aerodigestive diseases in dogs and comments on swallowing-related disorders that may result in respiratory pathologies.

In the ICU, oropharyngeal dysphagia can be broadly categorized as due to neurological dysfunction, structural alterations (e.g. trauma or masses), and toxins or drug side effects (e.g. drug-induced dysphagia). Neurological causes can be subdivided into those affecting the central nervous system, those affecting the peripheral nerve, those affecting the neuromuscular junction (e.g. myasthenia gravis), and primary myopathies. Critical illness can be extremely complex: more than one pathology can contribute to dysphagia. A list of diseases that have been associated with aerodigestive disorders in dogs is available.

Post-extubation dysphagia occurs in people. It is likely caused by multiple mechanisms, including direct trauma, neuromyopathy, depressed laryngeal sensory function, central neurological impairment, gastroesophageal reflux and breathing-swallowing dyssynchrony. Reported complications of endotracheal intubation in cats and dogs include tracheal rupture, necrosis and stenosis. Relevant reported complications in cats and dogs undergoing invasive critical care ventilation for ≥24 hours include regurgitation (12%), ventilator associated pneumonia (12%), oral lesions (including tongue swelling, ulcerations and ranula formation, 37%), leaking around the endotracheal tube cuff (15%), obstruction of the endotracheal tube (6%), dislodgement of the tracheostomy tube (3%) and hypoxaemia due to endobronchial intubation (1%). A literature search did not find reports of post-extubation dysphagia in cats or dogs.

Intensive care-acquired weakness is reported in humans. In humans, this acquired weakness may affect the muscles of swallowing. Similar signs are seen in critically ill animals (clinical experience): I have encountered dysphagia in critically ill dogs. One dog developed a radical change in the oral phases of swallowing and chronic regurgitation (dysphagia affecting phases 1, 2 and 4). The report detailing regurgitation in 12% dogs undergoing critical care ventilation did not note when regurgitation occurred or how long it was a problem for; it did not report other forms of dysphagia. Post-intensive care syndrome is a syndrome of long-term physical, cognitive and psychiatric impairments in humans following initial recovery from critical illness. Dysphagia is recognised as part of this syndrome. It might be that swallowing disorders in veterinary intensive care patients are under recognised.

Risk factors for aspiration related injuries in dogs have been reported and include “diminished consciousness, body position during anaesthetic recovery, duration of anaesthesia, vomiting and regurgitation, seizures, cranial nerve deficits, and the presence of megaoesophagus…” Of note for the emergency and critical care practitioner is canine geriatric onset laryngeal paralysis polyneuropathy and brachycephalic disease, as these patients may present with respiratory distress, laryngeal dysfunction (functional or structural) and oesophageal dysmotility.

The Mucociliary Escalator

Mucociliary clearance is an essential respiratory defence mechanism. The airway surface is the point of first contact for many pathogens, debris and chemicals. It serves as an essential barrier to protect the underlying structures and to clear materials from the lungs. Ciliated epithelial cells line the respiratory tract. Membranes involved in gas exchange are not ciliated. Coordinated beating of the cilia generates waves that elevate material up and out of the lungs and into the oropharynx to be swallowed. Coughing is additive to the clearance achieved via the mucociliary escalator.

Thus, coughing, swallowing and mucociliary clearance all work together to protect the respiratory system. Superficial to the cilia lies the airway surface layer, which consists of a thicker mucus layer atop a low viscosity periciliary layer. The two main mechanisms of mucociliary dysfunction include problems with ciliary function and airway surface layer alterations.

Cilia are motile, hairlike structures projecting from the apical membranes of epithelial cells into the airway lumen. They have a central microtubule scaffold called the axoneme. The axoneme consists of nine pairs of outer filaments attached to two inner filaments by radial spokes. In cross section, this looks like a bicycle wheel. Dynein, a motor protein, attaches the outer filaments and is responsible for energy production through ATP hydrolysis. Cilia beating is, therefore, an active process that requires a constant source of ATP.

Ciliary dyskinesia describes abnormal movement of the cilia. Primary ciliary dyskinesia (PCD) is caused by mutations in genes encoding structures of the axoneme or related proteins. Primary ciliary dyskinesia has been reported in dogs. In dogs and humans, frequent clinical signs include impaired airway clearance, chronic nasal disorders and recurrent lower respiratory tract infections starting in the early years of life. Primary ciliary dyskinesia may be under recognised in dogs.

Secondary ciliary dyskinesia (SCD) is perhaps more relevant to the critical care practitioner. Secondary ciliary dyskinesia is due to acquired, non-genetic defects in ciliary function. In humans, it occurs with smoking, chronic obstructive pulmonary disease and asthma. Specific pathogens, such as Streptococcus and Pseudomonas spp., mycotoxins released by Aspergillus spp., and a collection of respiratory viruses may cause SCD in people. Unlike PCD, abnormalities with SCD effect a smaller proportion of cilia (i.e., defects are local to the site of the primary pathology) and are thought to be reversible in most cases. Histopathological changes seen with SCD in dogs are variable.

The airway surface layer consists of a layer of mucus on top of a low viscosity periciliary layer (PCL). Mucus is produced by goblet and mucosal cells. It forms a gel overlying the airway luminal surface and traps pathogens and debris. It also contains antimicrobial substances and immunoglobulins A and G. Normal mucus is 97% water, 1% mucin, 1% salt and 1% other. The hydration status of mucus is very important and is controlled by chloride and sodium. The PCL submerges most of the cilia and provides a lubricating layer, allowing the cilia to beat easily. The PCL separates the mucus layer from the epithelial membrane, preventing mucus components adhering to and clogging the cilia. Hydration is again important and regulated by chloride and sodium. Cystic fibrosis in humans affects chloride transport into the airway surface layer, resulting in dehydration of the mucus layer and shrinkage of the PCL, making ciliary beating and airway clearance much more difficult.

Breathing dry air markedly decreases mucus clearance in dogs and leads to inflammation and sloughing of the epithelium. Breathing warmed and sufficiently humidified air (100% relative humidity) can avoid and reverse some of these changes—this is relevant when considering high flow (versus conventional low flow) nasal oxygen and mechanical ventilation. Endotracheal intubation impairs both the cough reflex and mucociliary clearance. Anaesthetic protocols containing ketamine decrease mucociliary clearance in mice, whereas protocols with fentanyl and propofol did not. Any compromise of the cilia or the airway surface layer compromises the mucociliary escalator and is a risk factor for respiratory pathologies.

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