Management of Dyspnea in the Terminally Ill

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Management of Dyspnea in the Terminally Ill

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Lara Pisani, MD, PhD; Nicholas S. Hill, MD, FCCP; Angela Maria Grazia Pacilli, MD; Massimiliano Polastri, MSc;

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and Stefano Nava, MD

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The genesis of dyspnea involves the activation of several mechanisms that are mediated and

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perceived depending on previous experiences, values, emotions, and beliefs. Breathlessness

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may become unbearable, especially in patients who are terminally ill, whether afflicted by

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respiratory-, cardiac-, or cancer-related disorders, because of a final stage of a chronic process,

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an acute event, or both. Compared with pain, palliation of dyspnea has received relatively little

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attention in clinical practice and the medical literature. This is particularly true when the

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breathlessness is associated with acute respiratory failure because most of the studies on

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pharmacologic and nonpharmacologic treatments of respiratory distress have excluded such

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patients. Assessments of the quality of dying for patients in an ICU consistently show that few

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patients are considered by family members to breathe comfortably at the end of their life. This

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review focuses on the management of dyspnea in patients with advanced terminal illness,

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summarizing clinical trial evidence on pharmacologic and nonpharmacologic interventions

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available for these patients.

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KEY WORDS:

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CHEST 2018;

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As summarized in an American Thoracic Society position paper on mechanisms of dyspnea in COPD, dyspnea is defined as “the subjective experience of breathing discomfort” and the physiology is complex.1 It involves the activation of several mechanisms that lead to increased work of breathing; stimulation of receptors in airways, lung parenchyma, or chest wall; and excessive stimulation of the respiratory

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cancer; COPD; dyspnea; noninvasive ventilation; opioids

“How people die lives on in the memories of those who live on” Cicely Saunders

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center by peripheral or central chemoreceptors. The sensation of dyspnea is also complex and is dynamically mediated and perceived depending on our previous experiences, values, emotions, and beliefs. Therefore, the symptom of dyspnea has subtypes that are described in different ways and derived from different respiratory and nonrespiratory disorders, as summarized in Table 1. Furthermore, as determined by PET scan, relief of dyspnea involves a characteristic brain activation different from that subserving dyspnea perception.2 We all

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ABBREVIATIONS: HFNT = high-flow nasal therapy; NIV = noninvasive ventilation; RCT = randomized controlled trial AFFILIATIONS: From the Department of Cardiac-Thoracic and Vascular Diseases (Dr Pisani), Respiratory and Critical Care Unit, University Hospital St. Orsola-Malpighi, Bologna, Italy; the Division of Pulmonary, Critical Care, and Sleep Medicine (Dr Hill), Tufts Medical Center, Boston, MA; the Department of Clinical, Integrated and Experimental Medicine (Drs Pacilli and Nava), Alma Mater Studiorum, University of Bologna, Bologna, Italy; and the Medical Department of Continuity of Care and Disability, Physical Medicine and

Rehabilitation (Mr Polastri), University Hospital St. Orsola-Malpighi, Bologna, Italy. CORRESPONDENCE TO: Stefano Nava, MD, Department of Clinical, Integrated and Experimental Medicine (DIMES) and University Hospital St. Orsola-Malpighi Department of Cardiac-Thoracic and Vascular Diseases, Respiratory and Critical Care Unit, Via G. Massarenti 9, Bologna 40138, Italy; e-mail: [email protected] Q5 Copyright Ó 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2018.04.003

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TABLE 1

] Subtypes of Dyspnea

Type of Dyspneic Sensation Air hunger

Origin of the Dyspneic Sensation Chemoreflex activity

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Pulmonary hyperinflation (COPD, advanced phase of asthma attack)

CPAP, NIV, bronchodilators

NIV, IMV

Chest tightness

Stimulation of slowly adapting receptors in the large airways

Bronchospasm (first phase of asthma attack)

Bronchodilators

Stimulation of pulmonary C fibers

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Muscle weakness (neuromuscular diseases)

Rapid breathing, tachypnea

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Interstitial lung disease, pulmonary venous congestion

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Opioids, HFNT

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HFNT ¼ high-flow nasal therapy; IMV¼ invasive mechanical ventilation; NIV ¼ noninvasive ventilation.

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experience dyspnea at times, for example during exercise, but in certain situations it becomes unbearable; therefore, it is not surprising that one of the most popular rating instruments (ie, Medical Research Council Dyspnea Scale) defines the highest stage of dyspnea as “too breathless to leave the house or dress or undress.”3 This is particularly relevant in patients who are terminally ill, whether afflicted by respiratory-, cardiac-, or cancer-related disorders, because of a final stage of a chronic process, an acute event, or both. In some acute or chronic situations, dyspnea results from a combination of events. Therefore, clinicians should evaluate the different onset of manifestation (chronic, acute on chronic, or end-of-life symptoms) to more effectively manage the dyspnea in these patients. In addition, many patients with advanced disease experience episodic dyspnea, which is poorly understood and often develops without any identifiable trigger.4 In this setting, the assessment of terminal dyspnea is a more complex process because the patient’s ability to perceive and report the symptom may be impaired in the face of declining cognition and alertness. Although interventions to alleviate breathlessness may or may not work in a particular patient, clinicians should feel obligated to assure these patients that beyond all the treatments that have been tried unsuccessfully to cure them, there will always be hope for a peaceful, dignified

death. Unfortunately, palliation of dyspnea has received relatively little attention in clinical practice, in medical literature, and (when we consider the emphasis given to the problem of pain) even among the general public. This holds particularly true when the respiratory distress is associated with acute respiratory failure because most if not all of the studies on the effects of pharmacologic treatments, such as opioids or oxygen, have excluded these patients. Therefore, it is not surprising that a study on the quality of the dying experience for patients in an ICU found that only 3% of patients were considered by family members to breathe comfortably at the end of life.5 Indeed, a study on patients who were terminally ill Q7 showed that breathlessness increased significantly at days 3 and 10 before death and remained unchanged thereafter; however, breathlessness was significantly higher for patients with noncancer diagnoses.6 Despite this finding, evidence shows that palliative care teams are seldom consulted in the terminal care of patients in the ICU or those with respiratory disorders.7 The aim of this review is to assess the pharmacologic and nonpharmacologic treatment of breathlessness, with specific emphasis on patients experiencing respiratory distress or acute respiratory failure at terminal stages of their disease. We also identify knowledge gaps and consider ways of improving the management of dyspnea in patients who are terminally ill.

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Materials and Methods

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Search Criteria

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This is a narrative review of the literature based on searches of two main databases, namely PubMed and The Cochrane Database of Systematic Reviews, using the key words “dyspnea,” “palliative dyspnea,” “breathlessness,” “palliative breathlessness,” and

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Possible Treatment

Activity of cerebral motor cortex

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Example of Disease

Increased work of breathing

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“refractory breathlessness.” The search strategy using Medical Subject Headings was limited to human studies and articles in English or in any other language with an English abstract. The search was done on abstract, title, and key words fields. Because this was a narrative review, we conducted a qualitative analysis without additional assessments.

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Results A total of 151 citations were retrieved using the Medical Subject Headings previously listed, including 134 citations on PubMed and 17 on The Cochrane Database of Systematic Reviews. Opioids

Mechanisms of dyspnea relief by opioids include the action on central receptors in the right posterior cingulate gyrus. At lower doses this mechanism does not necessarily alter respiratory drive, but respiratory depression and reduction of consciousness level can occur with larger doses.8 Thirteen out of 26 studies included in a recent Cochrane review9 on “opioids for the palliation of refractory dyspnea in adults with advanced disease and terminal illness,” assessed dyspnea during an exercise test, whereas the remaining studies, most of which had acute respiratory failure or distress as exclusion criteria, examined patients with end-stage cancer or noncancer patients. These studies used various medications (diamorphine, dihydrocodeine, morphine, and fentanyl), formulations (nebulized, subcutaneous, and oral), and schedules of administration (single dose vs multiple doses), limiting the conclusions or recommendations that can be made. Nevertheless, the Cochrane review concluded that some low-quality evidence shows benefit for the use of oral or parenteral opioids to palliate dyspnea, but no evidence to support the use of nebulized opioids. This is in keeping with the Canadian guidelines10 on managing dyspnea in patients with advanced COPD (grade of evidence 2C). Only one study has dealt with the management of dyspnea in patients with acute respiratory distress, with most patients also presenting with acute respiratory failure (mean SaO2 under oxygen, 92%).11 This randomized, placebo-controlled, and double-blind study aimed to assess the effect of nebulized morphine (10 and 20 mg) on dyspnea perceived at rest. Subjects benefited equally from nebulized saline or morphine via a placebo or other nonspecific effect, and nebulized morphine had no specific effect on dyspnea.

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However, despite the lack of clear scientific evidence, several international guidelines recommend the use of opioids in the management of dyspnea, and some of them also provide guidance for the protocol and dosage that should be used.1,12-16 For example, an advisory board of intensivists has suggested that “low and slow” intravenous titration of an immediate-release opioid,

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repeated every 15 min, should be provided until the patient reaches an acceptable level of symptom control.17 A continuous infusion may be substituted in the case of persistent dyspnea (Table 2).

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Why do we lack studies on opioids for acute respiratory failure? Opioids likely act both by depressing spontaneous respiratory drive and by modulating cortical activity, as they do in pain. A justifiable concern among clinicians is that opioids could thereby cause adverse events, including respiratory depression, confusion, and premature death in patients with respiratory failure. However, in a Swedish national prospective study, treatment with lower dose opioids was not associated with an increased risk of admission to hospital or death in patients who were oxygendependent, regardless of whether the patient was naive to opioids or had hypercapnia.18

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Nevertheless, half of Dutch chest physicians or residents in respiratory medicine rarely or never prescribe opioids for refractory dyspnea because of the fear of respiratory depression and adverse effects such as nausea and constipation and resistance on the part of the patient.19 This concern on the part of some physicians about the blunting effect of morphine on ventilatory drive may be excessive based on the greater relief of dyspnea TABLE 2

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] Suggested Morphine Protocol for the

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Management of Dyspnea in Opioid-Naive Patients Who Are Terminally Ill

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 Start therapy with morphine at low doses (1-2 mg IV), titrate up every 15 min until desired effect is achieved. In patients with severe dyspnea, may titrate more rapidly.

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 Monitor dyspnea, comfort, respiratory rate, and patient’s response with sedation scale (RASS).

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 In case of persistent dyspnea, switch to a continuous infusion.

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 It should be kept in mind that the correct dose and interval for opioid administration in all patients are those that relieve dyspnea without intolerable adverse effects.

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 Once the patient’s dyspnea has been controlled, maintain the effective basal infusion rate.

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 If patients experience significant opioid-related side effects, such as nausea and/or vomiting, consider reducing the morphine dosage or changing to an equianalgesic dose of hydromorphone (7 mg morphine to 1 mg hydromorphone).

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 Prevent opioid-associated constipation (laxatives or mu-opioid receptor inhibitors should be routinely prescribed).

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RASS ¼ Richmond Agitation-Sedation Scale. (Adapted with permission from Marciniuk et al10 and Lanken et al.12)

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compared with reduction of ventilation observed in a laboratory model of dyspnea in which moderate doses of morphine were administered to healthy individuals.20

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Benzodiazepines

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The use of anxiolytics to treat anxiety and panic may be helpful in relieving dyspnea.21 New instruments such as the Dyspnoea-12 and MDP allow multidimensional psychometric assessments of breathlessness that include sensory and affective components. Studies using these instruments suggest that anxiety can be the consequence of dyspnea or, in some cases, could be a contributing cause. In this way, benzodiazepines, by altering sensitivity perception, can reduce the patient’s response to dyspneic stimuli.22,23 In a recent Cochrane review24 on anxiolytic therapy for dyspnea, the authors identified eight studies for inclusion. The studies investigated small populations, used either alprazolam or diazepam, and comprised data from a total of 214 participants with advanced cancer or COPD, none of them with respiratory failure. Analysis showed no benefit of benzodiazepines for the relief of breathlessness. Furthermore, compared with morphine, no statistically significant effect was observed in the prevention of episodic breathlessness (breakthrough dyspnea) in patients with cancer. The benzodiazepines also caused significantly more adverse events when compared with placebo, particularly drowsiness and somnolence, but fewer when compared with morphine. Other anxiolytic drugs not included in the Cochrane review because of limited or conflicting evidence were selective serotonin reuptake inhibitors, antipsychotics, and tricyclics. Among these, chlorpromazine appeared to relieve dyspnea in an observational study performed in patients who were dying just before death.25 Although not considered in the Cochrane analysis because of a lack of evidence, the combination of opioids and sedatives is commonly used to treat dyspnea and anxiety at the end of life. One uncontrolled study that examined this combination (opioids and lorazepam) consisted mainly of patients with hypoxia (22/26 patients with an SaO2 < 90%) with severe dyspnea and related anxiety.26 It demonstrated not only a significant decrease in dyspnea and respiratory rate (40 breaths/min at baseline vs 30 breaths/min at 60 min), but also no effect on gas exchange. These results remark the relationship between anxiety and dyspnea and the positive effects of the combination of opioids and sedatives in selected patients, supporting the notion that dyspnea is a

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complex symptom resulting from multiple physiologic stimuli. A concern often raised about this combination is that it may shorten life. However, this possible outcome has been justified ethically by the principle of double effect, in which the shortening of life is acceptable if the primary aim is to bring comfort. There is, however, no solid evidence that initiation of treatment, or increases in the doses of opioids or sedatives, actually hastens death.27 In summary, benzodiazepines and other anxiolytics may be considered second- or third-line treatment when opioids and other nonpharmacologic treatments fail to provide adequate control of breathlessness, especially in patients who are very distressed and anxious.24 Sublingual or oral lorazepam (0.5-1 mg), subcutaneous or IV midazolam (1-2.5 mg), Q9 or in patients who are very distressed, a continuous subcutaneous or IV infusion of midazolam (10-20 mg over 24 h) may be added to opioid therapy.24 Of course, doses should be titrated to achieve the desired effect.

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Corticosteroids

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Corticosteroids are commonly used for palliative symptom relief in the treatment of patients with terminal malignant and nonmalignant diseases. The rationale behind the use of corticosteroids includes the reduction in airway inflammation and edema, which can lead to impaired lung function. Whether corticosteroids consistently achieve the desired palliative treatment goals remains controversial. An anonymous crosssectional survey in Japan showed that palliative care physicians perceived steroid treatment as efficacious for anorexia, fatigue, and dyspnea despite an awareness of the high prevalence and importance of serious adverse effects.28 A subsequent observational study demonstrated that although symptom scores improved with steroids for most patients with anorexia, nausea, pain, low mood, vomiting, and weakness, dyspnea did not improve.29 The only randomized controlled trial (RCT) on the effect of corticosteroids in patients with severe dyspnea found that dyspnea numeric rating scale scores were significantly reduced in the dexamethasone group but not in the placebo group and that the drug was well tolerated with no significant toxicities.30 Despite the evidence that many physicians perceive corticosteroids as useful to treat dyspnea in patients who are terminal, we find the evidence supporting their use in palliation of dyspnea quite weak and, with the exception of patients with severe airway or parenchymal lung involvement, would use them sparingly and with caution.

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Diuretics

IV use of loop diuretics may be helpful to decrease lung congestion in dyspneic patients with end-stage heart failure and lymphangitic carcinomatosis or in those patients whose chest lymphatics have been destroyed by radiation. In addition, nebulized furosemide has been tested as a novel approach to ameliorate dyspnea.31,32 Although its precise mechanism of action is still unknown, several animal and in vitro models suggest involvement of multiple mechanisms, including a protective effect against cholinergic, noncholinergic, and noradrenergic contraction of smooth muscle and activation of pulmonary stretch receptors and inhibition of vagal irritant receptors.33-35 In contrast with some previous positive reports,36,37 a small randomized controlled study by Wilcock et al38 demonstrated no evidence of benefit from 40 mg of nebulized furosemide on dyspnea in 15 patients with cancer. Also, two recent studies using aerosolized furosemide for dyspnea in a laboratory model showed no consistent effect in placebo-controlled trials with increasing doses and drugcontrolled delivery.39,40 Therefore, based on available data, the use of nebulized diuretics for the management of dyspnea in patients who are terminally ill is still controversial but cannot be recommended. Oxygen Therapy

Supplemental oxygen is commonly used as palliative treatment in end-stage patients because it is perceived by caregivers, patients, and families alike to offer a wide range of benefits. We will examine the evidence to support this practice from two different perspectives: (1) the use of standard oxygen via nasal cannula, Venturi, or non-rebreathing masks and (2) high-flow nasal therapy (HFNT), which consists of a heated and humidified gas mixture (FIO2 adjustable from 0.21 to 1.0) administered at flow rates up to 60 L/min via a specially modified soft, loose-fitting nasal cannula. Standard Oxygen: Long-term oxygen therapy has long been known to improve survival in stable patients with hypoxia and COPD, but its role in relieving dyspnea is still controversial.41 The relief of dyspnea in patients receiving oxygen therapy is thought to occur by directly reducing motor command output from the central controller.1 Other possible mechanisms are reductions of hypoxemia, serum lactic acid, and pulmonary artery pressure.1 In addition, supplemental oxygen (or medical air) via nasal cannula could stimulate upper airway receptors and reduce breathing drive, minute ventilation, and dyspnea independent of any effect on

PaO2.42 As shown by a recent meta-analysis, based on data collected in 33 RCTs (N ¼ 901), continuous oxygen during exertion relieved dyspnea in patients with COPD who would not otherwise qualify for home oxygen therapy because of mild or absent hypoxemia.43 In addition, the role of standard oxygen in alleviating cancer-related dyspnea was examined in another meta-analysis comprising 6 studies with a total of 179 patients.44 All studies were randomized and doubleblind (oxygen vs air cylinders and, in one trial, oxygen was compared with helium-enriched air or medical air). The duration of oxygen administration was usually very short (approximately 1 h), and it failed to improve dyspnea. Although the RCT by Abernethy et al45 had a longer duration of follow-up (7 days), no statistically significant difference was demonstrated between the effects of air vs oxygen on refractory dyspnea. Of note, only three of all the aforementioned investigations were performed in patients with hypoxia without COPD. Campbell et al46 randomly rotated 32 patients near Q10 death with respiratory failure (PPS # 30%) between medical air, low-flow oxygen, and no flow via a nasal cannula on an every 10-min basis. Study participants had been referred for palliative care consultation and had heart failure (25%), COPD (34%), pneumonia (41%), or lung cancer (9%). Most (91%) patients tolerated the protocol but registered no change in respiratory comfort during the different conditions. Repeated-measures analysis of variance revealed no differences in the Respiratory Distress Observation Scale, and the authors concluded that “oxygen is nonbeneficial for most patients who are near death.” In another crossover study examining the effect of oxygen supplementation in 14 patients with hypoxemic dyspnea caused by advanced cancer, Bruera et al47 randomized patients to receive either oxygen or air. After 5 min of stable oxygen saturation, patients were crossed over to receive the other treatment. The crossover was repeated twice. Dyspnea visual analog scale ratings were significantly better during oxygen treatment, and in a global rating questionnaire, patients reported little or no benefit during the air phase but moderate to much benefit during the oxygen phase. In yet another doubleblind, crossover trial examining the effect of nasal oxygen vs air on the relief of dyspnea in patients with advanced cancer, Philip et al48 found no significant difference between air and oxygen in a subgroup of 17 patients with acute hypoxia despite improvement in oxygen saturation when administered oxygen. As previously stated, the largest RCT49 was performed on

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patients with end-stage cancer with acute respiratory failure and compared standard oxygen vs noninvasive ventilation (NIV), and will be subsequently discussed in more detail. Despite the inferiority of oxygen in ameliorating dyspnea vs NIV, oxygen treatment was associated with a statistically significant improvement of dyspnea compared with baseline. The aforementioned studies differ substantially regarding patient populations enrolled and methods used to assess effects of oxygen and yielded conflicting results. Therefore, the evidence supporting the use of oxygen in patients with terminal cancer and dyspnea is not compelling. It is sufficient to support a trial of supplemental oxygen in such patients, especially if they are hypoxemic, but if patients are intolerant or not benefitting symptomatically, there is no reason to persist.

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HFNT: HFNT provides a number of beneficial effects, such as maintaining the integrity of mucociliary function by delivering heated and humidified gas at body conditions.50 This prevents airway exsiccation, renders secretions easier to mobilize, and reduces the metabolic cost of intrinsically heating and humidifying inhaled gas and the work imposed on muscles for expectoration.51,52 Another beneficial effect is the reduction in entrainment of room air compared with standard oxygen delivery systems because of the high flow rate of HFNT.53,54 Patients with respiratory distress can also benefit from washout of carbon dioxide from the anatomic dead space, which is greater at higher flow rates.55 HFNT also increases end expiratory pressure (approximately 1 cm H2O for every 10 L/min of gas flow with the mouth closed) and consistently lowers respiratory rate.56,57 As a consequence of these mechanisms, recent physiologic studies have observed that HFNT reduces work of breathing in patients with hypoxemic respiratory failure58 and patients with hypercapnic COPD.59 Other studies show that HFNT is associated with greater comfort and tolerance and less dryness of upper airways and dyspnea than conventional face masks.60-62

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Apart from an RCT comparing NIV with HFNT that will be subsequently discussed,63 only two observational studies have evaluated the use of HFNT in patients with respiratory distress, either with a DNI order or as a sole palliative tool. Peters et al64 found that HFNT improved oxygenation and dramatically reduced respiratory rate in 50 end-stage patients with severe acute respiratory failure, most with underlying respiratory disease, and the intolerance rate was < 20%. Using hospital charts, Epstein et al65 randomly selected 183 patients with

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respiratory distress and mainly with acute respiratory failure related to advanced malignancies. Patients had a variety of malignancies, including hematologic (29%); lung (17%); gastrointestinal (15%); sarcoma (6%); head, neck, and CNS (5%); breast (4%); and other tumors (24%). Of the patients, 78% died during the hospital stay. During use of HFNT, most patients had improved comfort and dyspnea (41%) or remained stable (44%), whereas only 15% deteriorated, with a median time on HFNT of 3 days. These preliminary studies on HFNT for palliation of dyspnea in patients with terminal conditions suggest that, by virtue of its physiologic and subjective advantages compared with standard oxygen, it may perform better in providing comfort and relief of dyspnea, but further controlled trials are needed to establish this possibility. Studies are needed to compare it with NIV as well. Table 3 describes how to apply and set HFNT in a palliative setting. NIV: NIV can help to reduce breathlessness by improving oxygenation, ventilation, resistive load on the ventilatory muscles, dynamic hyperinflation, and work of breathing. The Society of Critical Care Medicine66 charged a task force to provide guidance for the use of NIV in palliative care settings. The authors identified distinct goals for patients in palliative settings: (1) a scenario in which a patient has decided to forego intubation, but still wants to receive salvage NIV therapy with the goal of surviving the hospitalization, and (2) a scenario where patients seek symptom alleviation, mainly dyspnea, and survival is not a realistic goal for Q12 these patients (Table 4).67 Most of them, with the support of their families, are interested in having comfort while dying, but some may also be interested in

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TABLE 3

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] How to Apply and Set High Flow Nasal Oxygen Therapy in a Palliative Care Setting

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 Explain the procedure to the patient (if patient’s competence is not impaired).

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 Choose correct nasal cannula (small, medium, large).

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 Set temperature as tolerated (generally 34 C or 37 C).

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 Set flow rate (usual flow rates start at 45-50 L/min but may increase gradually up to 60 L/min, depending on level of patient’s comfort).

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 Set FIO2 as required (from 21% to 100%) to maintain desired SaO2.

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 Monitor dyspnea, comfort, respiratory rate, SaO2, and patient’s response. Provide support and make necessary adjustments to nasal prongs or device setup.

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TABLE 4

] Suggested Criteria for Starting and Discontinuing NIV in the Acute Setting

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When to Start  Tachypnea (with respiratory rate > 25 breaths/min)  Use of accessory muscles or paradoxical abdominal movements  Increased dyspnea—moderate to severe (ie, Borg score $ 3)  Orthopnea during sleep  Full comprehension of the rationale and goals of NIV in this setting by the patient and family members  The patient refuses the use of any pharmacologic treatment for dyspnea but is willing to try NIV When to Stop  The patient refuses to continue  Intolerance to the interface or ventilation which negates the palliative effect

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 Impaired mental status (Kelly score > 3)

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 Patient experiences no relief of dyspnea

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See Table 1 legend for expansion of abbreviation. (Adapted with permission from Cuomo.67)

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prolonging their lives for a few hours while maintaining cognition and the ability to communicate as they await relatives or to finalize their affairs. In this context, NIV would be considered effective if it improves breathlessness and respiratory distress without causing other troubling consequences. In the first scenario, one large observational study suggested that patients in whom NIV was a ceiling for therapy had the same benefit in quality of life as patients with no limitation, once they survived to hospital discharge.68 In the second scenario (NIV mainly used to ameliorate dyspnea), a pilot study performed in patients with solid cancer and respiratory failure, the use of NIV was feasible and effective in rapidly (within 1 h) ameliorating breathlessness, at least in most (62%) of the patients.69 In a similar study performed in an ED, more than half of the palliative group of patients failed to obtain dyspnea relief; therefore, NIV was suspended.70 A subsequent large multicenter study demonstrated a significantly greater reduction in dyspnea using NIV vs standard oxygen therapy, especially in the hypercapnic subgroup of patients.71 Interestingly, this investigation showed that NIV might reduce the dose of morphine necessary to palliate dyspnea, maintaining better cognitive function. Overall recruitment rate of the eligible patients for the protocol was 8.5%, with a dropout rate of 11% vs 0% in the oxygen group. It is noteworthy that although the dyspnea score (Borg) was significantly

improved compared with standard oxygen, it was quite high (4.2) even 48 h after enrollment, and dyspnea was, therefore, not under optimal control. In a similar population but without overt acute respiratory failure, Hui et al63 found comparable improvement in dyspnea scores and respiratory rate between NIV and standard oxygen, whereas NIV also had a similar patient-rated global symptom assessment compared with oxygen therapy. The application of inspiratory and expiratory assistance is important to reduce the inspiratory burden in this acute setting because the sensation of dyspnea correlates strongly with inspiratory load. Therefore, NIV could also be useful to relieve the sensation of dyspnea in severely distressed patients who are terminally ill. One caution in applying these results to other settings is that the investigations were performed in units very skilled with NIV; therefore, the results can be generalized only to similarly skilled units, including palliative care units. In addition, another important issue, particularly relevant in patients who are terminally ill, is the secretion removal and the inability to protect the airways when considering the use of NIV primarily for the palliation of dyspnea. Based on these findings, the NIV ERS/ATS Task Force Q13 suggested that despite the overall favorable results, the small number of studies, the heterogeneity in trial design, and the relatively low acceptance rate prevent a firm recommendation regarding the use of NIV as a palliative tool.71 Indeed, the task force emphasized the need for appropriate patient selection and staff training, especially where the use of NIV is not usual practice. In this regard, there is another important aspect which needs to be underlined. Although NIV is currently used in a wide range of settings, its successful application in the ED and in the nonpulmonary wards still remains controversial. In Table 4, we suggest criteria for starting and discontinuing palliative NIV in the acute setting.

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In 2008, a Cochrane review assessed the following nonpharmacologic interventions to treat dyspnea: single component interventions with subcategories of walking aids, distractive auditory stimuli, chest wall vibration, acupuncture/acupressure, relaxation, neuroelectrical muscle stimulation, fans, and several multicomponent interventions. Remarkably, these studies on miscellaneous treatments involved many more patients (> 2,500) than those previously described dealing with oxygen and respiratory aids.

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Obviously, some of these approaches, such as walking aids and Tai Chi, cannot be applied to patients with respiratory distress, and most of the studies were performed in patients with COPD. Breathing exercises as currently applied are unlikely to help patients who are terminally ill because they are usually performed over a period of weeks or months, there are no consistent favorable effects on dyspnea, and they may even increase work of breathing. 73

A recent review on 16 studies using acupuncture to treat dyspnea in stable patients found clinically important improvements. In particular, 68 patients with moderate-to-severe COPD were randomly assigned to a real acupuncture or a placebo needling group.74 After 12 weeks of treatment, the mean decrease in the Borg scale score after the 6-min walking test was significantly greater in the real acupuncture group than in the sham acupuncture group. One study considering 53 patients with cancer showed that guided imagery with theta music was a useful intervention for palliative care of patients with dyspnea.75 Theta music generates the theta rhythm, a neural oscillatory pattern in EEG signals that induces deep relaxation and may influence the sensation of breathlessness. A handheld fan blowing air on the face may also be a simple and alternative way to improve breathlessness. This is a very complex response that involves unclear mechanisms including the diving reflex, which allows aquatic mammals to stay underwater for extended periods of time by stimulating facial and nasopharyngeal receptors.42 This mechanism may provide the possibility to understand why many patients spontaneously report the need to sit or stand by an open window to reduce their perception of shortness of breath. In three RCTs evaluating this approach, fans reduced breathlessness and respiratory rate, one of these in patients who were dying.76-78

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studies included in the current review show that dyspnea can be managed in multiple ways, aiming to promote the best possible course in patients with end-stage diseases facing end of life. To choose the most appropriate approach or combination of interventions, clinicians should consider several aspects, including the underlying disease, the onset of symptoms, the stage and the trajectory of disease, and the emotional response of the patient. Palliation of dyspnea in patients who are terminally ill is an area that needs more attention in clinical practice and the medical literature. Future studies are required to target the therapeutic interventions on specific subsets of patients, according to the underlying mechanism of dyspnea.

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“Let us say only that I coughed, inhaled, and held my breath according to Hermogenes’ directions. He was alarmed, in spite of himself, by the rapid progress of the disease.It is difficult to remain an emperor in the presence of a physician, and difficult even to keep one’s essential quality as a man. The professional eye saw in me only a mass of humors, a sorry mixture of blood and lymph. This morning it occurred to me for the first time that my body, my faithful companion and friend, truer and better known to me than my own soul, may be after all only a sly beast who will end by devouring his master.I have no faith, however, as Hermogenes still claims to have, in the miraculous virtues of herbs, or the specific mixture of mineral salts which he went to the Orient to get. Subtle though he is, he has nevertheless offered me vague formulas of reassurance too trite to deceive anyone; he knows how I hate this kind of pretence, but a man does not practice medicine for more than thirty years without some falsehood. I forgive this good servitor his endeavour to hide my death from me. But no one can go beyond prescribed limits: my swollen limbs no longer sustain me through the long Roman ceremonies; I fight for breath; and I am now sixty.”79

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Conclusions

Acknowledgments

Dyspnea is a common symptom in patients with advanced terminal illness that compromises quality of life and causes distress in patients and family members. Because dyspnea is a multidimensional symptom resulting from multiple mechanisms, it may not respond equally to the different pharmacologic and nonpharmacologic treatments. Therefore, a comprehensive multidisciplinary approach, composed of physical, emotional, social, and spiritual aspects of refractory breathlessness, is recommended. In fact, the

Authors contributions: S. N. takes full responsibility for the content of the manuscript, including the data and analysis. L. P., N. S. H., A. M. G. P., M. P., and S. N. have made substantial contributions to the interpretation of the data and critically revised the manuscript for important intellectual content. L. P. and M. P. have made substantial contribution concerning literature search, writing, data analysis, and study design. N. S. H., A. M. G. P., and S. N. have made substantial contributions concerning data interpretation, data analysis, and critically revising for important intellectual content. All authors have provided final approval of the version to be published and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Financial/nonfinancial disclosures: None declared.

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