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Wien Med Wochenschr (2009) 159/23–24: 583–590 DOI 10.1007/s10354-009-0727-z Springer-Verlag 2009 Printed in Austria
Management of dyspnea in patients with chronic obstructive pulmonary disease Amy P. Abernethy1, Hope E. Uronis1, Jane L. Wheeler1 and David C. Currow2 1
Division of Medical Oncology, Department of Medicine, Duke University Medical Center (DUMC), Durham, North Carolina, USA 2 Division of Medicine, Department of Palliative and Supportive Services, Flinders University, Bedford Park, South Australia, Australia Received September 1, 2009, accepted (after revision) October 13, 2009
Behandlung der Atemnot bei Patienten mit chronisch obstruktiver Lungenerkrankung Zusammenfassung. Die chronisch obstruktive Lungenerkrankung (chronic obstructive pulmonary disease [COPD]) ist eine fortschreitende und schwächende Erkrankung, die weltweit zunehmend an Bedeutung gewinnt. Zusätzlich zur Basistherapie der Erkrankung erlangen palliativmedizinische Interventionen zur Symptomkontrolle besonders in fortgeschrittenen Stadien eine große Bedeutung. Nach Ausschöpfung der Basistherapie ist bei Patienten in fortgeschrittenen Stadien der COPD Symptomkontrolle als primäres Ziel einer erfolgreichen Behandlung anzusehen. Dyspnoe ist das am meisten belastende Symptom von COPD-Patienten. Wenn die Dyspnoe nicht mehr durch Ausschöpfung der Basistherapie bzw. Akuttherapie erleichtert werden kann (z. B. bei refraktärer Dyspnoe), verlagert sich das Ziel der Behandlung. Im Mittelpunkt stehen nun nicht mehr die Lebensverlängerung, sondern optimale Symptomkontrolle, verbesserte Funktionen und gesteigerte Lebensqualität. Um dieses Ziel zu erreichen, stehen zahlreiche pharmakologische und nicht-pharmakologische Interventionsmöglichkeiten zur Verfügung, deren Evidenz jedoch unterschiedlich bewertet wird. Dieser Review stellt einen Überblick von Behandlungsmöglichkeiten der refraktären Dyspnoe von COPD-Patienten im Bezug auf vorhandene Daten dar und beleuchtet Gebiete, die weiteren Untersuchungen bedürfen. Behandelte Themen sind Sauerstoff, Opioide, Psychotropika, inhalatives Furosemid, Heliox28, Ernährung, psychische Unterstützung und Atemtechniken. Schlüsselwörter: Chronisch obstruktive Lungenerkrankung (MeSH), Dyspnoe (MeSH), Palliativmedizin (MeSH), schmerzlindernde Medikation, Opioid (MeSH), Sauerstoff (MeSH)
Correspondence: Amy P. Abernethy, MD, FAAHPM, Duke University Medical Center (DUMC), Box 3436, Durham, NC 27710, USA. Fax: þþ1-919-684-5325, E-mail:
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Summary. A progressive and debilitating illness, chronic obstructive pulmonary disease (COPD) has major worldwide impact. In addition to the care for underlying causes of disease, COPD treatment involves palliative intervention to address associated symptoms; in later stages of disease, when the underlying disease has been maximally treated, symptom management assumes primacy as the goal of care. Dyspnea is the most distressing symptom experienced by COPD patients. When dyspnea cannot be relieved by traditional COPD management strategies (i.e., refractory dyspnea), the goal of care shifts from prolonged survival to minimized symptoms, improved function, and enhanced quality of life. Numerous pharmacologic and non-pharmacologic interventions are available to achieve these goals, but supporting evidence is variable. This review summarizes options for managing refractory dyspnea in COPD patients, referring to the available evidence and highlighting areas for further investigation. Topics include oxygen, opioids, psychotropic drugs, inhaled frusemide, Heliox28, nutrition, psychosocial support, and breathing techniques. Key words: Chronic obstructive pulmonary disease (MeSH), dyspnea (MeSH), palliative care (MeSH), analgesics, opioid (MeSH), oxygen (MeSH)
Introduction The fourth leading cause of death worldwide [1], chronic obstructive pulmonary disease (COPD) is an international health problem with global prevalence of approximately 9–10% among adults 40 years of age [2]. By 2020, worldwide, COPD is projected to be the fifth leading cause of disability-adjusted life years lost [3, 4]. COPD remains a progressive, incurable illness. The 2001 Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) guidelines 583
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recommend a stepwise approach to care because lung function declines and patients become more symptomatic. Therapeutic interventions added to treatment regimens include bronchodilators, anti-cholinergic agents, pulmonary rehabilitation, inhaled glucocorticoids, and oxygen [5]. Smoking cessation is the only intervention known to slow progression of the disease [6, 7]. Management of dyspnea in the context of COPD treatment, relying primarily on bronchodilators, is discussed elsewhere; this paper focuses instead on strategies for managing dyspnea when the underlying disease has been maximally treated. Overall, the trajectory of COPD is characterized by intermittent worsening followed by improvement in performance status, with an overall progression toward complete disability and death [8, 9]. Over time, quality of life diminishes, largely due to increasing dyspnea. As treatment options for COPD itself are exhausted, conventional methods of alleviating dyspnea by modifying the disease begin to fail; comfort becomes more difficult to achieve. Care of these patients is challenging because of the difficulty of identifying end-stage patients who might still benefit from palliative interventions.
Dyspnea: definition and mechanisms The symptom of dyspnea is difficult to understand and define, for both physicians and patients. It manifests as an experience of breathlessness created by a sensation involving activation of neural pathways, tempered by the patients perception [10]. Patients descriptions of dyspnea vary widely, in part on the basis of the individuals underlying disease, ethnic/racial background, previous experiences, and emotional state. To establish a common definition that accounts for this variation, a consensus panel of the American Thoracic Society articulated the following definition of dyspnea: a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses [10]. The pathophysiologic mechanisms underlying the development of dyspnea have yet to be clarified. In current understanding, dyspnea results from a mismatch of respiratory motor activity and incoming afferent activity, including information from chemo-, vagal, mechano-, pulmonary stretch, and muscle receptors 584
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[10]. The mechanistic interactions among factors are not yet well understood, and certain puzzling scenarios suggest that other factors may be involved. For example, dyspnea is associated with increase in PaCO2 as well as decrease in PaO2 and/or pH detected by peripheral chemoreceptors; however, not all patients with abnormal blood gas levels experience dyspnea, and many dyspneic patients have normal blood gas levels [11, 13].
Goals of palliative interventions for intractable dyspnea Patients whose dyspnea cannot be alleviated through further treatment of their COPD are said to have intractable or refractory dyspnea [14]. In this substantial – and growing – population of patients, COPD has been maximally treated but breathlessness persists. Patients may complain of dyspnea that seems out of proportion to apparent physical disability or functional impairment. Here the goals of care become relief of breathlessness and improvement in function rather than extension of survival. Palliative treatments can improve symptoms and quality of life for COPD patients with intractable dyspnea. This review outlines the principal options, discusses the data behind them, and provides practical guidance. Incorporating this information into clinical practice first requires clear articulation of the goals of therapy. It is assumed here that extending survival is not the primary goal of therapy. Instead, therapeutic interventions are examined in terms of their impact on the sensation of breathlessness and/or functional status.
Pharmacologic interventions Approaches to the management of refractory dyspnea have focused on several primary options: opioids, psychotropic drugs, inhaled frusemide, and Heliox28 [15]. To date, is the strongest evidence supports the use of opioids (oral, parenteral), but the data have not yet been sufficient to indicate use of nebulized opioids, anxiolytics, selective serotonin reuptake inhibitors (SSRIs), inhaled frusemide (also known as furosemide), or Heliox28, and the data do not support the use of phenothiazines. Oral and parenteral opioids Although opioids have been used for many years to relieve refractory dyspnea, this practice remains Springer-Verlag
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controversial. Safety is the primary concern, with the predominant risk being respiratory depression [5, 16]. The mechanism of action of opioids in alleviating dyspnea is poorly understood; they may act centrally, peripherally, or by reducing anxiety [17]. Evidence has confirmed that opioids reduce ventilatory response to carbon dioxide [18], hypoxia [19, 20], inspiratory flow-resistive loading [21], and exercise. Morphine has been shown to decrease oxygen consumption in healthy individuals both at rest and with exercise [22]. A systematic review and meta-analysis found that oral and parenteral opioids exert a highly statistically significant effect on the sensation of breathlessness (overall pooled effect size 0.31, 95% confidence interval [CI] 0.50 to 0.13, p ¼ 0.0008), although the clinical effect was relatively small (approximately 8 mm on a 100 mm VAS with baseline levels of dyspnea of 50 mm) [23]. The authors gave several reasons for this small effect: opioid doses were often low, doses were not titrated, dosing intervals were long, and single-dose studies would fail to achieve steady state. Their analyses did not suggest that the use of opioids was associated with changes in arterial blood gas measurements or oxygen saturation. Building upon this foundation, a subsequent trial evaluated the impact of oral morphine on opioid-naïve adults with refractory dyspnea [14]. Forty-eight outpatients with refractory dyspnea were enrolled in an eight-day randomized, double-blind, crossover study of 20 mg once-daily sustained-release oral morphine sulfate or placebo. The primary outcome was the sensation of breathlessness measured on a 100 mm visual analog scale (VAS). Participants were elderly (mean age 76, standard deviation [SD] 5); 71% were receiving oxygen therapy; mean baseline morning dyspnea score was 43 (SD 26). Patients receiving morphine had a significant decrease in dyspnea, with mean improvements in dyspnea intensity of 6.6 mm in the morning (p ¼ 0.011) and 9.5 mm in the evening (p ¼ 0.006), indicating a relative improvement over baseline dyspnea of 15–22%. Morphine did not depress the respiratory rate (RR; mean RR for morphine vs. placebo ¼ 20 [SD 5] vs. 21 [SD 4], p ¼ 0.143). No episodes of severe sedation or obtundation were recorded. The main side-effect was constipation (9 vs. 1, p ¼ 0.021), but neither treatment caused more vomiting, confusion, sedation, or appetite suppression. Patients who received morphine described better sleep at night (p ¼ 0.039). In practice, when a patient with refractory dyspnea is opioid-naïve, the clinician starts with a 20-mg, once-daily, sustained-release, oral morphine preparawmw
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tion provided the patient has no contraindication to morphine. When this preparation is unavailable, a 15-mg, twice-daily, long-acting morphine product can be substituted, initially once a day and increasing to twice daily after 5–7 days if the patient tolerates the medication and has residual breathlessness. When the patient has a contraindication to morphine, the clinician prescribes long-acting oxycodone starting at 10 mg once a day and increased to twice a day after 5–7 days as tolerated and needed. Alternatively, hydromorphone dosed around the clock might be used in analgesic doses equal to 20–30 mg of morphine. It is advisable not to start with the 25-mg fentanyl transdermal patch as this provides over 80 morphine equivalents per day. If an opioid-tolerant patient is already on a regular dose of morphine or another opioid, the opioid can be sequentially increased by 20% of the total daily dose every 3–5 days until the breathlessness is relieved or side-effects occur [24]. Psychotropic drugs Psychotropic agents are used to treat refractory dyspnea based on the assumptions that (a) dyspnea contains a large psychological component, and (b) anxiety contributes significantly to the associated functional impairment [25]. Anxiolytics, phenothiazines, and selective serotonin reuptake inhibitors (SSRIs) are the principal psychotropic drugs used in dyspnea management. Benzodiazepines Studies of benzodiazepines have been small and somewhat inconclusive. An exploratory study reported beneficial effect in four patients [26], but two subsequent studies failed to replicate these results [27, 28]. Several other studies investigated the effectiveness of alprazolam, a shorter acting and potentially less-sedating medication than diazepam; one controlled study [29] found no improvement in breathlessness, while a case report documented benefit [30]. In a randomized controlled trial in terminally ill cancer patients of morphine 2.5 mg every four hours, midazolam 5.0 mg every four hours, or the combination, the combined intervention provided the greatest relief of breathlessness [31]. Side-effects, especially sedation, were worst in the morphine-only arm, potentially due to the bolus rescue doses provided according to the study protocol. Importantly, this trial focused on very sick individuals in the last days of life with Karnofsky performance status scores in the 20% range, so results may not be appropriate and transferable to other palliative care populations. Abernethy et al. – Dyspnea management in COPD
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Practically, when anxiety obviously and substantially aggravates dyspnea, the clinician can prescribe benzodiazepines. Since midazolam carries risk and may not be allowed in some clinical areas, alprazolam is generally preferable as a shorter acting product, or clonazepam is for longer acting control. Other anxiolytics Animal studies have shown buspirone, a serotonergic anxiolytic agent, to be a respiratory stimulant [32, 33]. Two small studies in human patients with severe COPD evaluated the effects of buspirone on breathlessness, exercise tolerance, and anxiety [34, 35]. These studies included slightly different patient populations; eligibility criteria for one, but not for the other, required baseline anxiety. The studies yielded conflicting results, one finding improvement in all three domains, and the other finding no difference. These data, while inconsistent, suggest a possible role for anxiolytic agents in selected patients with refractory dyspnea. In practice, an n of 1 trial is advisable for patients who are potential candidates for these agents; each patient should be carefully monitored for benefit (relief of breathlessness, improvement in function) without excessive adverse effects. When an identicalappearing placebo is not available, a single-sided n of 1 trial may be the best approach, with outcomes carefully documented for review in concert with the patient and caregivers (e.g., family member, close friend, or other person providing informal care). Selective serotonin reuptake inhibitors (SSRIs) SSRIs attracted attention in the 1990s for their potential to alleviate breathlessness. A pilot study reported improvement in six patients (three of whom had psychiatric disorders) after six weeks of sertraline [36]. In a case series of seven patients with obstructive lung disease treated with sertraline, three of whom met criteria for panic disorder, all patients reported a decrease in breathlessness and several also reported improvements in exercise tolerance; there were, however, no formal measures performed [37]. SSRIs may improve dyspnea and exercise tolerance by relieving anxiety symptoms, by direct effect on respiration, or both. Many patients with dyspnea, which seems disproportionate to their pulmonary compromise, experience depression and/or anxiety; data suggest that treating these symptoms relieves dyspnea [38]. Animal data suggest that serotonin acts at the level of the brainstem respiratory center, and this action may 586
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affect the sensation of breathlessness [39]. Currently, the evidence is insufficient to recommend SSRIs for relief of dyspnea in the absence of an underlying psychiatric diagnosis. Inhaled frusemide Owing to its low chloride content, frusemide inhibits the cough response [40], and exerts a preventive effect on bronchoconstriction in patients with asthma [41–43]. Inhaled frusemide may also act indirectly on the vagally mediated sensory nerve ending in the airway epithelium [44]. Inhaled frusemide has been studied in healthy individuals [45] and in COPD patients [46]. In healthy individuals, it prolongs breath-holding time and the period of no respiratory sensation, and slows the onset of discomfort during loaded breathing [45]. A systematic review that included 42 articles published between 1988 and 2004 reported that, although nebulized furosemide appeared to have a positive influence on dyspnea and physiologic measurements, studies to date of this agent primarily came from small-scale clinical trials or observation trials. While this intervention appears to hold promise for the treatment of dyspnea, the evidence is not yet sufficient to establish its benefit. Heliox28 A mixed gas, Heliox28 contains 72% helium and 28% oxygen. A Phase II crossover study evaluated breathlessness during a six-minute walk test while 12 lung cancer patients with refractory dyspnea breathed Heliox28, 28% oxygen, or medical air [47]. Patients scored their breathlessness significantly lower on a VAS when breathing Heliox28 compared to medical air (40.2% [SD 4.8] vs. 59.3% [SD 5.3], p < 0.05); there was no significant difference (VAS, Borg) in breathlessness when patients breathed Heliox28 vs. oxygen (47.0% [SD 5.6]) or oxygen vs. medical air. Patients walked farther when breathing Heliox28 than oxygen (214.2 m [SD 9.6] vs. 174.6 m [SD 11.2], p < 0.05) or medical air (128.8 m [SD 10.3], p < 0.0001). This study suggests a potential role for Heliox28 in the management of refractory dyspnea, but the evidence remains scant. Cost and feasibility issues may limit the usefulness of this alternative in patients with advanced COPD.
Oxygen therapy Long-term oxygen therapy is indicated for patients with severe hypoxemia (i.e., resting Springer-Verlag
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PaO255 mmHg); this treatment improves survival, dyspnea, and functional status [48–50]. In patients with advanced life-limiting illness, regardless of PaO2, palliative oxygen is frequently prescribed to manage dyspnea [51, 52]. Over 70% of physicians caring for dyspneic palliative care patients report prescribing oxygen, usually for refractory symptoms (65%) or at patient request (30%) [53]; in one study, over 40% of patients receiving long-term oxygen therapy did not meet current guidelines [49]. Belief in the effectiveness of palliative oxygen for relief of breathlessness is widespread. In an email survey of palliative care specialists and respiratory physicians in Australia and New Zealand, 58% of 214 respondents (69% of palliative medicine clinicians and 48% of respiratory physicians surveyed) reported a belief that palliative oxygen is beneficial; 65% of respondents cited intractable dyspnea as the most common reason for prescription [53]. Canadian clinicians reported similar convictions [54]. A recent international double-blind randomized controlled trial was conducted to determine the effectiveness of palliative oxygen vs. medical (room) air, delivered by concentrator, for relief of breathlessness in patients with life-limiting illness, refractory dyspnea, and PaO2 > 55 mmHg (results presented in abstract form only, with manuscript submitted). Patients were recruited from outpatient pulmonary, palliative care, oncology, and primary care clinics at 9 sites in Australia, United States, and England; of the 239 participants, 64% had COPD. Neither medical gas proved superior. Over the 7-day intervention period, mean morning and evening dyspnea scores on a 0–10 numerical rating scale (NRS) decreased by 0.81 (SD 2.6) and 0.40 (SD 2.1), respectively (p < 0.001), regardless of intervention, reflecting 18% and 9% relative improvement with either medical gas; quality of life showed parallel improvement (p < 0.001). Most improvement in dyspnea occurred within the first 3 days; e.g., 55% of improvement in evening dyspnea was in the first 24 hours and 88% in the first 72 hours. Baseline dyspnea predicted improvement; participants with moderate (4–6 NRS) and severe (7–10 NRS) baseline dyspnea had average decreases in morning dyspnea of 1.0 and 1.3, respectively. These results suggest that a medical gas may help some patients, especially those with more severe baseline breathlessness, and that a therapeutic trial of 3–4 days should suffice to identify patients who may benefit. Currently, standard practice is to first establish the goals of therapy as relief of dyspnea, improvewmw
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ment in function, and improvement in quality of life. Then, a blinded n of 1 trial is conducted with oxygen or medical air delivered at 2 liters per minute. A respiratory therapist or nurse administers the gas for 15 minutes, randomly choosing oxygen or air without revealing the assignment to the clinician or patient. The patient undergoes a 5-minute wash-out period before the other gas is administered. If access to medical air is not available, the test can be conducted using a fan as the comparator (note that this unblinds the trial). The patient scores his/her dyspnea on a VAS or NRS. If function is a major concern, assessment should include a baseline exertional test consistent with the patients best functional status (i.e., shuttle test [55], three-minute walking test, reading a paragraph aloud). The same functional test is repeated after 10 minutes on each gas. Unblinded results are reported to the clinician and patient. If the patient has superior results on oxygen, a prescription for palliative oxygen is written after a careful discussion about cost. If air is superior, a fan is prescribed. If both are equally helpful, then the patient chooses. Patients receiving oxygen are asked to evaluate quality of life improvements and therapyrelated limitations over one week; this experience guides the decision as to whether to continue or discontinue the intervention. Clinicians should bear in mind that oxygen therapy is not without burden; people may have a sense of being tied to a machine, develop anxiety about power supply, and limit excursions outside the house.
Non-pharmacologic interventions Several alternatives to treatment with drugs or oxygen have been investigated for their role in assisting patients with the symptoms or burden of dyspnea. Two of the most promising strategies are psychosocial support and breathing techniques. Psychosocial support In COPD, where symptoms and functional deterioration can cause significant distress to patients and caregivers, psychosocial support is an important component of care and becomes more important as patients decline and experience greater functional limitation. Here the interventions seek to help patients cope with their illness and the changes it entails in their lives, and to help caregivers navigate the changes in roles and relationships that result as disease progresses and symptom burden increases [17]. Abernethy et al. – Dyspnea management in COPD
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Several qualitative studies have examined the support needs of caregivers for dyspneic individuals. In one study, the investigators interviewed 10 COPD patients and their caregivers; many caregivers reported that taking care of a breathless person was pre-occupying, restricting, and a major cause of anxiety. The investigators concluded that clinicians must not forget about the needs of their patients families and that patients with disabling symptoms are often best managed using a multidisciplinary approach that includes psychosocial care [56]. A similar study, also describing the experiences of 10 patients with COPD and their caregivers, found that caregivers experienced losses similar to those of the patients, felt burdened by multiple roles, and felt an unfairness that strained the patient/caregiver relationship [57]. Existing guidelines do not stipulate protocols for psychosocial care of patients with dyspnea or their caregivers. Clinicians caring for dyspneic COPD patients must evaluate and attend to needs for increased psychosocial support, and respond to patient/family concerns when they arise with appropriate intervention and/or referral.
Breathing techniques Controlled breathing techniques, notably positioning and pursed lip breathing (PLB), are useful for managing dyspnea. In the most commonly used breathing position to alleviate breathlessness, the forward-leaning position, patients lean forward (e.g., onto a table) and support their weight with their arms and upper body. This posture increases abdominal pressure and may improve respiratory muscle function [58]; it has also been reported to improve inspiratory muscle strength [59] and diaphragmatic function [60], reduce the use of accessory muscles, and decrease abdominal breathing [60–62]. In PLB, the patient inhales through the nose and then exhales slowly, usually for four to six seconds, through pursed lips. By stenting the airways and preventing dynamic airway collapse, PLB decreases air trapping [63]; it often helps to avert panic attacks that accompany severe breathlessness [64]. While studies have demonstrated the benefit of these techniques for relieving dyspnea in controlled research settings, results in actual clinical practice are variable [58]. Given the potential benefit of breathing techniques, clinicians are advised to provide dyspneic COPD patients with instruction in positioning and PLB, and to review their skill with this technique as well as perceived benefit during subsequent clinic visits. 588
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Nutrition Malnutrition is not uncommon in patients with COPD and weight loss can become severe as disease advances. Consequences of this loss include weakness of inspiratory and expiratory muscles which can lead to impaired lung function [65]. Studies have demonstrated a link between malnutrition and impaired pulmonary status [66] as well as with increased mortality [67]. However, a meta-analysis of 11 randomized, controlled trials studying the effects of nutritional supplementation in patients with severe COPD found no significant effect on any outcome variable, including anthropomorphic measures, pulmonary function, respiratory muscle strength, functional exercise capacity, and health-related quality of life [68]. Only three trials [69–71] evaluated quality of life or dyspnea, so it is difficult to draw conclusions regarding the effect of nutrition on dyspnea in patients with end-stage COPD.
Conclusions Intractable or refractory dyspnea contributes substantially to the suffering of COPD patients. As individuals continue to live longer, the number of endstage COPD patients will increase; for these patients, the goal of palliative interventions is to decrease symptoms, and to improve functional status and quality of life. Several treatment options are available. The most evidence supports oral or parenteral opioids, particularly morphine, for relief of breathlessness. Palliative oxygen delivered via concentrator, or medical air perhaps through use of a fan, may benefit some patients, particularly those with severe breathlessness; an n of 1 trial should guide the clinical decision. Owing to limited and sometimes conflicting data, anxiolytics and selective serotonin reuptake inhibitors have limited utility; they should be approached cautiously until more information is available. Evidence is inconclusive as yet for Heliox28, though feasibility issues may limit its utility regardless of benefit. Inhaled frusemide and nutritional intervention both require further evidence before they can be advocated. Finally, instructing the patient in positioning and pursed lip breathing constitute simple no-cost interventions with potential to be very effective.
Conflict of interest The authors declare that there is no conflict of interest. Springer-Verlag
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