Dyspnea, cough, anorexia, fatigue, anxiety, and depression are symptoms commonly experienced by patients with advanced diseases of the respiratory system. Though by varying mechanisms, diseases affecting the respiratory system including chronic obstructive pulmonary disease (COPD), interstitial lung diseases, primary lung malignancies, and other cancers with metastases to the lungs may present with these clinical manifestation that may worsen with progression of disease. Comorbid conditions, in particular congestive heart failure, also can contribute to worsening of dyspnea.

The most common symptom in all respiratory diseases is dyspnea. The term dyspnea originates from the Greek roots dys, meaning painful or difficult and pneuma, meaning breath to describe the symptom of breathlessness or difficulty breathing in healthy individuals and people with diseases affecting the respiratory system [1, 2]. Treating persistent dyspnea becomes increasingly important as activities of daily living become impaired, and progression of this symptom is a better indicator of progression of disease than formal testing including lung function studies. This is underscored by a study on dyspnea in COPD showing dyspnea to be a better predictor of health-related quality of life (HRQOL) and mortality than severity of airflow limitation [3].

The sensation of dyspnea can be separated into two components comprised of “air hunger,” or the urge to breathe, and the sense of excessive effort of breathing [4]. Due to the nature of dyspnea as a visceral sensation rather than a localized, peripheral sensation, the exact mechanisms of dyspnea are incompletely understood. Activation of limbic, paralimbic, and cerebellar structures has been identified on MRI during dyspnea [5]. Activation of these primitive regions of the cerebral cortex has also been demonstrated with pain, hunger, and thirst, consistent with the idea that these structures play a role during any urgent homeostatic imbalance to counteract a threat to survival.

The pathophysiology is theorized to result from a disassociation between central respiratory motor activity and afferent information from receptors in the lungs, airways, and chest wall, which in turn stimulate respiratory-related neurons in the brainstem. Heightened ventilatory demand may be induced by hypoxia, hypercapnia, metabolic acidosis, and exercise [6]. Increases in ventilation are required to compensate for the enlarged dead space from pulmonary disease; however, patients with advanced disease are often deconditioned due to prolonged inactivity. Deconditioning is associated with higher lactate levels, which in turn increases ventilation with exercise and worsens the sensation of dyspnea [7]. This cycle of deconditioning leading to further dyspnea is seen in functional decline with normal aging as well as advanced pulmonary disease.

Measurement of dyspnea is subjective and can be rated on a scale from 1 to 10, similar to a pain rating scale. A numerical rating scale for dyspnea (NRS-D) and a visual analog scale for dyspnea (VAS-D) have been developed and are commonly used. The Modified Borg Scale has descriptors associated with each of the numbers [8]. Alternatively, a scale such as the Medical Research Council (MRC) Breathlessness Scale might be used—it suggests five different grades of dyspnea based on the circumstances in which it arises [9]. In palliative patients with lung cancer, the English version of the cancer dyspnea scale has been found useful [10]. Dyspnea is also routinely assessed during a general palliative care symptom assessment using the Edmonton Symptom Assessment Scale [11].

Supplemental oxygen is routinely offered to dying patients with dyspnea, but its value in relieving symptoms in non-hypoxemic patients has been questioned [12]. The goal of oxygen therapy is to decrease hypoxic drive mediated by peripheral chemoreceptors in the carotid body in hypoxemic patients. Reducing chemoreceptor activation will cause decreased ventilation. Oxygen may also blunt pulmonary artery pressure rise associated with strenuous activity. While benefit of supplemental oxygen to improve exercise tolerance has been shown for mildly hypoxemic COPD patients, studies of COPD patients without resting hypoxemia showed no significant improvement in exercise tolerance or dyspnea with supplemental oxygen [10, 13, 14]. In patients with advanced cancer in a hospice setting, supplemental oxygen was found to be equally effective as room air in reducing dyspnea, with improvement in dyspnea unrelated to a subject’s initial level of hypoxia [13, 15, 16]. It is possible that the perception of airflow alone led to subjective improvement in dyspnea [17]. This might also be accomplished with the use of fans; however, few high quality studies are available [18]. Supplemental oxygen therapy was found to have no effect in palliative patients with normal blood oxygen saturations in a double-blind, randomized controlled trial [12]. However, the clinical practice of offering oxygen to dying patients despite lack of evidence is commonplace and may be due to practical issues: in most hospice settings pulse oximetry is not used and thus differentiating which patients are hypoxic and might benefit from oxygen therapy from those who are not is not possible. If supplemental oxygen is administered, via nasal cannula is preferred over facemasks which can interfere with eating and talking. Noninvasive positive pressure ventilator support (NPPV) can treat dyspnea in COPD patients but it is often poorly tolerated or perceived as uncomfortable, and occasionally anxiety-provoking [19–23]. Physical inactivity has also been demonstrated to increase perception of dyspnea in COPD [12]. While patients with advanced pulmonary disease will likely have limited exercise capacity, exercise programs tailored to one’s capabilities may offer some benefit in alleviating dyspnea [15].

Other non-pharmacologic interventions for dyspnea in advanced malignant and non-malignant diseases with at least some evidence of effectiveness are chest wall vibration, neuro-electric muscle stimulation, and breathing training [24]. Chest wall vibration (CWV) is thought to stimulate afferent impulses from intercostal muscles on cortical centers, reflex suppression of brainstem respiratory output, and decrease the sense of respiratory effort. Tidal volume has been shown to significantly increase following therapy [23]. In neuromuscular electrical stimulation (NMES) electric impulses are used to elicit muscle contraction. This therapy has been used in severe COPD patients to increase muscular oxidative capacities to help facilitate rehabilitation in patients with incapacitating dyspnea which has shown to improve muscle strength and endurance, exercise tolerance, and breathlessness during activities of daily living in small studies [26]. Breathing training may include techniques such as pursed-lips breathing (PLB) which attempts to prolong active expiration through constricted lips. Compared with spontaneous breathing, PLB has shown to decrease the respiratory rate and dyspnea as well as improve tidal volume and oxygenation at rest [27]. There is low evidence for benefit of acupuncture and acupressure, and not enough date available to evaluate the benefit of relaxation techniques, fans, counseling and support, or distractive auditory stimuli [28]. Though further studies are needed to validate these non-pharmacologic treatment options, patients should be evaluated on an individual basis for treatment in the setting of progressive symptoms despite pharmacologic agents.

The two groups of medications used to treat dyspnea are opiates and anxiolytics. Opioids have long been established as an effective treatment in relieving dyspnea in COPD patients, patients with advanced cancer, and terminally ill patients [2, 29–31]. Opiates have been shown to decrease ventilation at rest and during submaximal levels of exercise, modulate dyspnea in acute bronchoconstriction, and may blunt or suppress perception of respiratory sensation [32]. Nearly all routes of administration are effective; only nebulized morphine has been shown to have no effect on dyspnea in several studies [33, 34]. The most common side effects are seen on initiation of therapy and are dose dependent, with the most frequent side effects observed including constipation, nausea, and somnolence. Appropriately titrated, opiates have been shown to be safe and effective for dyspnea due to multiple etiologies [1, 2, 30, 35, 36]. Opioid-naïve patients will usually respond to low doses of oral or parenteral morphine; higher doses are necessary for those on chronic opioids and must be individually titrated. Acute severe dyspnea should be rapidly treated with parenteral opioids, and some patients may require continuous infusion of a basal rate. Some clinicians hesitate to use opiates for dyspnea (or pain) due to unfounded concerns about respiratory depression, a quite rare event that is preceded by drowsiness; thus it is always advisable when ordering opioids to specify “hold for sedation/difficulty arousing patient.” Opiates can be titrated to effect, e.g., goal is to reduce a dyspnea score to 3 or below. Dying patients who no longer can self-report dyspnea can be assessed by looking for distress like gasping or grimacing and opioid titration can follow the respiratory rate, e.g., with a goal to reduce respiratory rate to 20s or close to normal.

Dyspnea is frequently associated with or exacerbated by anxiety. Anxiolytics have been proposed to relieve dyspnea by depressing hypoxic or hypercapnic ventilatory responses as well as treating underlying anxiety that may contribute to a sensation of dyspnea. Benzodiazepines have been most frequently studied anxiolytics for use in dyspnea with no benefit found in patients with dyspnea due to advanced cancer or COPD [37]. However, one study with buspirone, an anxiolytic with no sedative effects, found significant improvement in depression and anxiety, as well as improved exercise tolerance and dyspnea following treatment [38]. Further studies are needed to assess the benefit of anxiolytics in treatment of dyspnea in advanced lung diseases.

Imminently dying patients are unable to clear secretions and have impaired cough and gag reflexes. Saliva accumulated in the posterior oropharynx and secretions in the tracheobronchial tree can lead to ‘noisy breathing’ and sounds resembling choking that can be distressing to families. This ‘death rattle’ and should be thoroughly explained to families; it does not always warrant treatment as there is no evidence that it is distressing to the patient. Repositioning the patient can lead to postural drainage and improve symptoms; anticholinergic medications like atropine, scopolamine, or glycopyrrolate are often used if the family finds it too distressing [39, 40].

Another common and very bothersome symptom in advanced airway diseases is cough.

A cough is defined as a deep inspiration followed by a strong expiration against a closed glottis. While identified as a prevalent symptom in COPD, cough has not been shown to have the same association with the degree of airway obstruction as progressive dyspnea. Cough is independent of severity of disease due to a heightened cough reflex sensitivity in both COPD and asthma, by which the sensitivity of the lining of the airways results in medulla-mediated afferent impulses of the vagus nerve resulting in cough. Cough, anorexia, fatigue, and anxiety are all frequently reported symptoms of patients with advanced airway diseases, though may have a smaller relative contribution to disability.

Cough is a complex physiological reflex initiated by activation of vagal afferent nerves innervating the airways and lungs [7]. Afferent pathways from receptors in and under the epithelium of the airways are rapidly adapting and can be stimulated directly by tussive agents which can be either chemical or mechanical irritants [41]. Though cough is a defense mechanism, modulation of the cough reflex pathway in disease states can lead to an augmented cough response, as seen in COPD and asthma [42, 43]. Disease states specifically cause an increase in sensitivity of rapidly adapting irritant receptors (RARs) in the tracheobronchial tree and C-fiber receptors located in laryngeal, bronchial, and alveolar walls. RARs are normally silent, but when activated cause rapidly adapting discharges with an irregular pattern that are conducted in vagal nerve fibers, provoking cough. RAR stimulants include cigarette smoke, ammonia, ether vapor, acid and alkaline solutions, hypotonic and hypertonic saline, and mechanical stimulation by catheter, mucus, or dust. RAR activity is enhanced by pulmonary congestion, atelectasis, bronchoconstriction, and decreases in lung compliance [2, 31]. C-fiber receptors have thin nonmyelinated vagal afferent fibers and are activated by the same stimuli as RARs. However, their activation does not induce cough, but instead release tachykinins such as substance P, which in turn stimulate RARs to cause cough.

In severe COPD and other advanced pulmonary diseases in a palliative setting, opiates have been established to be effective therapy. Opiates are thought to inhibit cough by affecting primarily the μ-opioid receptor in the central nervous system. Morphine, codeine, and dihydrocodeine may be considered goal standard narcotic antitussive agents [22, 23]. Studies in palliative cancer patients have validated the efficacy and safety of hydrocodone as treatment for cough, though the same rate of efficacy has not been consistently shown in patients with COPD [44, 45].

Mucolytics have not been found to consistently ameliorate cough. Cough suppressant therapy is found most effective for short-term reduction in coughing only. These drugs are non-specific, intended to suppress cough regardless of etiology. These drugs target multiple mechanisms of cough by affecting mucociliary factors (i.e., guafenasin), the afferent limb of the cough reflex (dextromethorphan), the central mechanism for cough (opioids), the efferent limb of the cough reflex (baclofen), and skeletal muscles (succinylcholine, propofol) [46].

In addition to pulmonary manifestations, patients with advanced pulmonary diseases develop systemic complications including anorexia, weight loss, cachexia, and muscle wasting. Pulmonary cachexia is recognized feature of COPD, with the exact mechanism in this disease poorly understood. Potential factors include oxidative stress, inflammation, and muscle wasting. Muscle wasting has been demonstrated in COPD due to alterations in protein synthesis [47, 48]. Whole-body protein synthesis is depressed, accompanied by an overall fall in whole-body protein turnover. However, skeletal muscle dysfunction, independent of lung function, has been shown to contribute significantly to decreased exercise capacity and a poor quality of life [49]. Limb and skeletal muscle dysfunction is exacerbated by low-grade systemic inflammatory processes, malnutrition, corticosteroids, hypoxemia, oxidative stress, protein degradation, and changes in vascular density. Muscular remodeling has been observed in COPD by means of fiber-type redistribution [50]. The proportion of type-I fibers was found to be markedly lower in COPD, with a higher proportion of type-II fibers, which have a lower oxidative capacity. In further studies, reduced oxidative capacity has grossly been demonstrated in patients with moderate to severe COPD [42, 43]. Additionally the capillary to fiber ratio in muscles from subjects with COPD was found to be reduced [51]. While other alterations in the mechanisms of protein degradation and synthesis are still being investigated, it is evident that skeletal muscle dysfunction separate from muscle wasting contributes significantly to the progression of symptoms and decline in quality of life in those with COPD.