Keywords

advanced disease, dyspnea, interventions

 

Authors

  1. Campbell, Margaret L. PhD, RN, FPCN
  2. Donesky, DorAnne PhD, ANP-BC
  3. Sarkozy, Alexandra MSI
  4. Reinke, Lynn F. PhD, ANP-BC, FAAN, FPCN

Abstract

Dyspnea is a subjective experience of breathing discomfort that consists of qualitatively distinct sensations, varies in intensity, and can only be known through the patient's report. Dyspnea is akin to suffocation and is one of the most distressing symptoms experienced by patients with advanced illness and at the end of life. Common approaches to dyspnea management, such as pulmonary rehabilitation, breathing strategies, or supplemental oxygen, have become accepted through pragmatic use or because studies do not include dyspnea as a measured outcome. Patients and clinicians urgently need evidence-based treatments to alleviate this frightening symptom. To fill this gap, a group of dyspnea researchers with expertise to conduct a literature review of evidence-based interventions for dyspnea in patients with serious illness produced these guidelines. We present the evidence from the strongest recommendations for practice to the weakest recommendations and include practical considerations for clinical nurses.

 

Article Content

Dyspnea is a subjective experience of breathing discomfort that consists of qualitatively distinct sensations, varies in intensity, and can only be known through the patient's report.1 Dyspnea is akin to suffocation and is one of the most distressing symptoms experienced by patients with advanced illness and at the end of life. The prevalence is high across diagnoses, with the greatest prevalence among patients with cardiopulmonary diseases.2 The trajectory of dyspnea remains high in the last 90 days for patients with chronic obstructive pulmonary disease (COPD) and escalates in the last weeks for patients with lung cancer.3 Patients across diagnoses experience an escalation in respiratory distress in the last week of life.4

 

Common management approaches for dyspnea include pulmonary rehabilitation, breathing strategies, supplemental oxygen, opioids, and nonpharmacologic strategies. Many of these approaches have become accepted through pragmatic use or because of evidence that does not include dyspnea as a measured outcome. A new clinical practice guideline focused on dyspnea in oncology will be published by the American Society of Clinical Oncology in spring 2021.5 Other associations have previously published guidelines or statements on dyspnea.1,6,7 However, the search criteria for those publications excluded some articles that may have a smaller sample size, specific diagnosis or setting, or lower level of evidence but still provide suggestions of dyspnea interventions of interest to palliative and hospice nurses that may prove beneficial in an "n of 1" setting with individual patients.8 Patients and clinicians urgently need evidence-based treatments to alleviate this frightening symptom. The purpose of this review was to critique the evidence about treatment of dyspnea in the context of advanced disease and at the end of life, from the perspective of hospice and palliative care nurses with dyspnea expertise.

 

METHODS

The literature search was conducted in 2 stages, During stage 1, the literature from 1990 to 2015 was searched in PubMed, CINAHL, and the Cochrane Collaboration databases by a research librarian (A.Z.), and dyspnea nurse experts (M.C., D.D., E. Fahlberg, D. Thorpe, A. Walsh, L.F.R.) (Figure 1).9 Search terms included dyspnea, dyspnoea, breathless, respiratory distress, advanced disease, COPD, heart failure, lung cancer, dementia, ALS, end of life, refractory, opioids, benzodiazepines, bronchodilators, anticholinergics, oxygen, medical air, bipap, cpap, fans, positioning, and interventions. The initial search yielded 486 articles from which 269 duplicates were deleted. During stage 2, the literature from 2016 to 2019 was searched in PubMed and yielded 290 additional articles. After being hand filtered by methodology for randomized controlled trials (RCTs), systematic reviews, original research articles, and narrative reviews, 55 articles from the stage 2 search were submitted for review.

  
Figure 1 - Click to enlarge in new windowFIGURE 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) flow diagram.

We determined that studies would be included for critique if they were full research reports, systematic reviews, or meta-analyses in which treating dyspnea was the primary or secondary study aim and dyspnea was explicitly measured. Articles that reported pilot study results when a fully powered report was available were excluded. After using these criteria in an abstract and title review, the total number of articles from both searches narrowed to 148. Following full-text review and with the addition of 8 articles that were identified through review of reference lists, 102 articles met the inclusion criteria. Levels of evidence were adapted from the Oncology Nursing Society Putting Evidence into Practice Classification (Table 1).10

  
Table 1 - Click to enlarge in new windowTABLE 1 Levels of Evidence

Each article was reviewed by 2 reviewers. The intervention, comparator, location and setting, study design, population, sample size, dyspnea measure, quality of evidence, and study findings were extracted during each review and placed in an Excel file (Microsoft, Seattle, WA). In a series of conference calls, 6 reviewers who are expert hospice or palliative care nurses discussed each study selected during the 2015 search until consensus was reached on the quality of the evidence. For the subsequent 2019 update to the literature search, 2 authors (L.F.R., D.D.) reviewed titles and abstracts and integrated the additional articles that met the inclusion criteria into the review. Although the purpose of this article is not to provide guidelines or recommendations for practice, we organized the article from the strongest to the weakest evidence, based on the Putting Evidence into Practice Classification (Table 2).10

  
Table 2 - Click to enlarge in new windowTABLE 2 Summary of Interventions

STRONG EVIDENCE

Immediate-Release Opioids

Several studies demonstrate the effectiveness of oral morphine for the treatment of acute episodic dyspnea in patients with advanced cancers, COPD, and those with chronic pain.11-13 Oral morphine immediate release (IR) for patients with heart failure has mixed results14 but is likely to be effective. The mechanism of action for morphine is binding to and activating the [mu]-opioid receptors in the central nervous system. Opioids are postulated to alter central mechanisms; in other words, opioids deceive the brain into responding to a different threshold for hypoxemia or hypercarbia and to alter volitional breathing.15-17 A systematic review conducted by Jennings et al11 in which 11 of the 18 studies included patients with COPD confirmed overall benefits of oral opioids compared with placebo on dyspnea. Of note, 14 of the 18 RCTs involved single dosing of opioids. Based on this evidence, oral morphine IR administered at low doses, for acute episodic dyspnea, up to 30 mg daily, is effective for dyspnea relief.

 

The recommendation for oral morphine and also dihydrocodeine, a semisynthetic opioid analgesic commonly used as an antitussive, is supported by findings from a systematic review comparing oral or parenteral opioids with placebo for patients with refractory breathlessness in advanced lung disease or terminal illness.18 Among 18 RCTs, the mean change from baseline dyspnea score improved in the opioids group compared with the placebo group indicating benefit; however, dose recommendations were not provided because of significant heterogeneity among the trials.18 Clinical guidelines recommend initiating oral doses at 5 mg (morphine equivalent) every 4 hours with an additional equivalent dose every 1 to 2 hours as needed.19 Tolerance may develop in long-term use because of changes in opioid receptor sites including neuroadaptation and desensitization. Studies have been limited to morphine, fentanyl, and dihydrocodeine by oral and parenteral routes. Gaps remain regarding other formulations and routes, and populations other than COPD, cancer, or chronic pain.

 

Oxygen to Correct Hypoxemia

Oxygen is a disease-modifying treatment that corrects hypoxemia leading to a reduction in hypoxemia-induced dyspnea. Hypoxemia is understood to be an arterial oxygen tension (PaO2) of less than 55 mm Hg or an oxygen saturation (SpO2) of less than 85%.20 Prior evidence among patients with COPD supports the use of supplemental oxygen to correct dyspnea in patients with chronic hypoxemia.21,22

 

Fan Directed to the Face

Fans are inexpensive and easy to use across diagnoses and settings of care, do not require a prescription, and do not induce clinician's fears regarding safety such as often occurs with the use of opioids. The mechanism of action is unknown but postulated to be from multiple factors related to stimulation of facial temperature receptors.23,24 Randomized trials and systematic reviews of patient perceptions constitute the evidence base in support of using a fan aimed toward the cheeks for a duration of 5 to 10 minutes for the relief of dyspnea.25-29 A battery-operated handheld fan is convenient, or a table or wall-mounted fan may be useful when the patient cannot hold a battery-operated fan, as long as the flow is directed to the face.

 

Long-Acting Bronchodilators for COPD

Patients with advanced COPD are likely to be on long-acting bronchodilators when they are referred to palliative care or hospice. These agents should be continued and titrated as needed to control dyspnea and prevent episodes of acute distress.30 Combination therapy of long-acting [beta]-adrenergic agonists (eg, salmeterol) plus long-acting muscarinic antagonists (eg, tiotropium) provides better control than either agent alone.31-35 Therefore, patients on a single bronchodilator without adequate dyspnea control may experience greater relief if a second type of bronchodilator is added. Hospice patients with COPD should be continued on their bronchodilators, both long-acting and short-acting, as long as possible; inhaled medications used for symptom relief are covered by the Hospice Medicare Benefit. As the patient declines and becomes unable to manipulate an inhaler, nebulized aerosol treatments provide access to the medication by breathing normally through a mouthpiece or mask without any required coordination. Evidence for the use of long-acting bronchodilators in non-COPD conditions that produce dyspnea could not be found.

 

Pulmonary Rehabilitation

Pulmonary rehabilitation, which includes exercise training, has become the standard of care for patients with COPD, and it has become increasingly accepted for the care of patients with dyspnea related to other serious illnesses, including interstitial lung diseases.36 Wadell and colleagues37 demonstrated that pulmonary rehabilitation primarily improves the affective and functional components of dyspnea, whereas the sensory component remains unchanged. Pulmonary rehabilitation is usually accessed in the presence of moderate to severe COPD and other illnesses; the effect of exercise or pulmonary rehabilitation on dyspnea late in the disease trajectory of COPD is unknown. The long-term effects of pulmonary rehabilitation on dyspnea are also unknown. However, a systematic review and meta-analysis of 15 exercise training RCTs with patient-reported outcomes in patients with advanced cancer documented statistically significant reduction in dyspnea after 0.5 to 6 months of exercise training for the 8 RCTs (n = 564 patients) that reported on dyspnea as an outcome.38

 

LIKELY TO BE EFFECTIVE

Sustained-Release or Subcutaneous Opioids

Studies conducted by Abernethy et al39 confirmed the effectiveness of once-daily dosing of morphine sustained release (SR) for improving refractory dyspnea and sleep and for heart failure. The mechanism of action is the same as morphine IR. The most commonly reported adverse effects are constipation, drowsiness, nausea, and vomiting. Bowel regimens including laxatives and stool softeners should be routinely prescribed to prevent constipation. There were no reports of hospitalizations for respiratory depression or decreased levels of consciousness. A recent randomized placebo-controlled trial confirmed there were no treatment-emergent adverse events from regular, low-dose morphine (SR) in patients with chronic breathlessness.40 Morphine SR once daily is not available in the United States; therefore, 15 mg twice-daily dosing up to 30 mg is recommended.39,41 Subcutaneous morphine for patients diagnosed with advanced lung cancer18,42,43 is likely to be effective. A systematic review and meta-analysis found no evidence of clinically significant adverse events of opioids (varying formulations, dosages, and routes) for chronic breathlessness including respiratory depression, increase in arterial carbon dioxide tension (PaCO2), increase in end-tidal carbon dioxide tension (PEtCO2), decrease in PaO2, or decrease in respiratory rate.44 These findings may allay clinician's fear of prescribing opioids for patients with chronic breathlessness.

 

Short-Acting Bronchodilators for COPD

Short-acting [beta]-adrenergic agonists (eg, albuterol) and short-acting muscarinic antagonists (eg, ipratropium) are likely to be effective in relieving dyspnea in COPD, particularly in acute symptom distress, as these are generally considered "rescue" agents. According to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, "Short-acting inhaled [beta]2-agonists, with or without short-acting anticholinergics, are recommended as the initial bronchodilators to treat an acute exacerbation" of COPD.45(p98) Therefore, these should be included in the palliative symptom management plan for acute dyspnea exacerbations.

 

Breathing Management Techniques

Positioning and posture are reported to be helpful for patients with dyspnea. Although respiratory mechanics are improved in the sitting position compared with supine in patients with stable heart failure, there is no difference in dyspnea.46 A single patient training session of breathing management techniques, including breath control, pacing, relaxation, and anxiety management, may be effective for dyspnea management.47

 

Eight weeks of high-intensity interval inspiratory muscle training (IMT), supervised weekly by a physical therapist, resulted in clinically and statistically significant improvement in dyspnea as measured by the London Chest Activity of Daily Living Scale in 19 patients with advanced lung disease.48 Patients with COPD (n = 11), interstitial pulmonary fibrosis (n = 3), bronchiectasis (n = 3), or asthma, many of them awaiting transplant, participated in 2 sessions of IMT per day with 30 fast forceful inspirations using the PowerBreathe K3 (HaB International Ltd, Southam, United Kingdom) flow resistive loading device with load starting at 50% of mean inspiratory pressure and adjusted to maintain dyspnea at 4 to 6 on the modified Borg scale during training sessions. Although a control group was not available and additional testing is necessary, these results support IMT as a viable adjunct to improve dyspnea in patients with advanced lung disease.

 

Home-Based Exercise

An internet-based dyspnea self-management program that included coaching for home walking has been tested with equivocal results.49-51 The intervention included home-based exercise, nurse coaching, and dyspnea self-management administered online using chat rooms, discussion forums, and online exercise and symptoms logs.49 Dyspnea improved within all groups, including the control group, with no difference between internet and face-to-face groups.

 

Patients with COPD who self-selected to purchase a lower limb cycle machine and participate in tailored self-management education experienced similar decline in dyspnea measured by the Modified Medical Research Council as that in patients in the usual exercise control group.52 Patients in the intervention group were encouraged to use the cycle machine for at least 20 minutes per day with intensity measured by dyspnea between 3 and 4 on the modified Borg scale. No measure of exercise adherence was reported. Six-minute walk distance was maintained over 3 years for the intervention group but significantly declined in the control group. Given the tendency for patients to control their dyspnea during exercise, the increased 6-minute walk distance indicates improved functioning for the same level of dyspnea. Further study of this intervention is indicated.

 

Breathlessness Intervention Programs

Three UK-based breathlessness intervention programs consistently demonstrate improvement in dyspnea and distress for patients with advanced cancer and other advanced lung diseases.53-55 These programs provide 2 to 6 home or clinic visits and telephone calls by an interprofessional team over a period of 6 weeks. Depending on the needs of the patient, the interventions include exercise prescription, breathing strategies, fan, pacing, and an action plan. An individualized Australian 6-week breathlessness intervention that included education, a handheld fan, and a written breathlessness plan documented improvement in average and worst breathlessness on a numeric rating scale (NRS) for patients with severe COPD.56 Retrospective analysis of 45 patients with COPD who were treated in a Canadian dyspnea clinic identified 21 responders with clinically significant improvement in dyspnea as measured by Edmonton Symptom Assessment Scale at the 2-month follow-up visit.57 The goal of the clinic was to optimize respiratory mechanics, reduce the increased drive to breathe without compromising ventilation, and improve quality of life through individualized treatment plans in patients with COPD with dyspnea despite optimal pharmacotherapy. Interventions offered through the clinic included optimization of disease-specific pharmacotherapy including comorbid treatment, opioids and oxygen therapy, referral for pulmonary rehabilitation or community-based palliative care, sleep hygiene, psychosocial support and panic control, noninvasive ventilation (NIV), and home equipment to assist with mobility and safety.

 

A systematic review of holistic services for breathlessness, mostly related to advanced cancer, revealed significant reductions in distress due to breathlessness as measured on the NRS.58 Interventions included within the definition of "holistic services" included information and education related to nutrition; sleep hygiene; smoking cessation; psychosocial support; self-management strategies that included breathing techniques, emergency preparation, exercise, handheld fans, pacing, positioning, and relaxation techniques; and other interventions such as acupressure or transcutaneous electrical nerve stimulation (TENS), occupational aids, or pharmacological review. Ten studies measured breathlessness intensity with a variety of tools using various definitions of breathlessness, which prevented synthesis of the results. As health care systems in the United States are implementing chronic care management programs, breathlessness programs could serve as a care model for patients with dyspnea.

 

Acupoints and Acupressure

A single session of TENS over acupoints (acuTENS) produced a statistically significant improvement in dyspnea among patients with COPD compared with placebo.59 Four weeks (20 sessions) of acupressure was associated with significant improvement in dyspnea compared with sham pressure points.60 Although the optimal procedure, timing, and specific acupoints need to be specified, the evidence suggests that stimulating acupoints is associated with relief of dyspnea in COPD. There may be a cultural influence on the results of these studies. Studies with other disease populations could not be found.

 

BENEFITS BALANCED WITH HARM

Noninvasive Ventilation

Only one study was found measuring the effectiveness of NIV in a palliative context. As expected, patients with hypercarbia had a significant reduction in dyspnea.61 Noninvasive ventilation can produce a number of adverse effects including mask intolerance, mask interference with eating, drinking and speaking, and sleep disturbance; thus, use should be goal-based and balanced with harm. In addition, if the NIV settings are not optimized to the patient's ventilation demands, dyspnea may be increased. If a short-term trial of NIV does not reduce dyspnea, other palliative alternatives should be considered.62

 

High-Flow Nasal Oxygen

High-flow nasal oxygen (HFNO) of up to 60 L/min may offer symptomatic improvement to a more diverse patient population with dyspnea because the delivery system does not cover the mouth and may affect multiple mechanisms of action.63,64 An observational study of hospitalized patients outside of critical care revealed improved dyspnea with HFNO in 90 of 111 patients with median dyspnea visual analog scale (VAS) scores improving from 8 (6-9) prior to HFNO administration to 5 (4-6, P < .001) with HFNO.65 Some patients are unable to tolerate HFNO because of skin irritation, nasal dryness, gastric distension, or epistaxis. Initiation of HFNO in patients with refractory hypoxemia will lead to subsequent patient-surrogate decisions about ceasing treatment. Home-based products are becoming available that can produce up to 30 L/min for those patients who can achieve dyspnea relief at settings lower than those achieved in the acute care setting.

 

Nutraceutical: Coenzyme Q10

Very few studies on the effect of nutritional supplementation on dyspnea have been published. One Italian study of coenzyme Q10 and creatine supplementation on outcomes related to COPD documented statistically significant improvements in multiple dyspnea measures after 2 months. The safety profile was not reported.66

 

Acupuncture

There was no improvement in dyspnea for acupuncture compared with placebo for advanced cancer.67 However, 2 nonrandomized pre-post studies of acupuncture have shown statistically significant improvement in dyspnea as part of an Edmonton Symptom Assessment Scale symptom cluster in patients with cancer68 or those enrolled in hospice.69 Unlike acupressure or acuTENS, acupuncture involves needles piercing the skin, which can lead to bruising, bleeding, soreness, and possibly even needles breaking off in the skin or infection if needles are not sterile. In addition, acupuncture is performed only by specially trained individuals.

 

Palliative Bronchoscopic Interventions

Chart review of 105 patients who received palliative bronchoscopic interventions because of benign inflammatory or malignant airway narrowing showed significant improvement in dyspnea measured by NRS immediately after the intervention.70 Two patients experienced intraprocedural bleeding that required intensive care unit care. Other complications included temporary oxygen desaturation, stent malpositioning, edema, or delayed recovery from anesthesia.

 

A large RCT testing the effects of bronchoscopic lung volume reduction with Zephyr endobronchial valves (Pulmonx Corporation, Redwood City, CA) for patients with hyperinflated emphysema demonstrated statistically and clinically significant improvement in dyspnea measured by multiple validated surveys including St George's Respiratory Questionnaire, COPD Assessment Tool, and Transitional Dyspnea Inventory. Improvements in breathlessness, activity, and psychosocial parameters lasted up to 12 months.71 Although only a select group of patients qualify for invasive lung volume reduction procedures, these results hold promise to improve quality of life for patients with emphysema.

 

EFFECTIVENESS NOT ESTABLISHED

Opioid Formulations, Routes, and Diagnoses

Systematic reviews of opioids for the treatment of dyspnea in patients with interstitial lung diseases include small samples of patients72; therefore, the effectiveness of oral morphine IR for dyspnea relief in these patients is not established. Eiser et al73 tested the effect of diamorphine on improvement in exercise tolerance for patients with emphysema. Findings did not support the use of diamorphine for improvement of dyspnea during exercise as measured by a VAS. Nebulized fentanyl,74 oral transmucosal fentanyl,75 or intravenously administered fentanyl76 has not been established to be effective for patients with advanced cancers or lung diseases. A recent retrospective study examining the effect of intravenously or subcutaneously administered fentanyl among patients with advanced cancers (n = 72) near the end of life found a significant reduction in dyspnea at rest. Controlled trials are needed to establish effectiveness.77

 

A recent study found no difference in the reduction of breathlessness now in morphine (SR) compared with placebo.78 Both groups were allowed to take 6 doses or fewer per day of 2.5 mg morphine (IR) as needed. A group from Denmark pilot tested a morphine/hydrochlorate oral solution that contained ethanol agent compared with morphine solution without ethanol on 12 patients with advanced cancers. The morphine/hydrochlorate oral solution containing ethanol decreased breathlessness measured by the NRS within 3 minutes faster compared with the morphine solution without ethanol. The authors posit that ethanol facilitates faster absorption in the mouth.79 These results identify the need for further studies to define the optimal dose and formulation of morphine and target populations with severe breathlessness.

 

Benzodiazepines

Although widely used in practice,80 equivocal results were found with regard to benzodiazepines as a primary treatment for dyspnea.12,43,81,82 No new evidence about benzodiazepine use to treat dyspnea in COPD and cancer was reported in a 2016 systematic review.83 Benzodiazepines are recommended as second- or third-line treatment when opioids and other therapies have failed to relieve dyspnea.83 Usefulness of midazolam as an adjunct to morphine was reported in a single study84 and may be related to improvement in the anxiety related to dyspnea.

 

Oxygen Without Hypoxemia

Several underpowered trials of oxygen compared with medical air among patients with cancer yielded no differences in dyspnea.85-87 Patients admitted to the hospital with acute heart failure (n = 50) were randomized to either high (>=96%) or low (90%-92%) SpO2 targets for 72 hours with no subsequent difference in dyspnea VAS (P = .86).88 A large multinational RCT of long-term oxygen for COPD, including the use of supplemental oxygen for exertion only, did not result in sustained benefits with regard to mortality, first hospitalization, or functional status. This study challenges the long-held belief that long-term oxygen in COPD reduced mortality; surprisingly, dyspnea was not measured.89

 

Nebulized Diuretics

Based on the review criteria, 3 articles were identified examining the use of nebulized diuretics in relieving cancer-related dyspnea. These small studies did not provide sufficient evidence to establish the effectiveness of this intervention.90-92 A randomized crossover study of 12 healthy volunteers who inhaled 40 mg furosemide while inspiratory flow and tidal volume were controlled on a mechanical ventilator showed that the subjects experienced 20% reduction in breathing discomfort due to hypercapnia.93

 

Vaporized Cannabis

Bronchodilator effects of cannabis were reported in the 1970s, but subsequent research has not been done. A group of Canadian researchers explored the effect of vaporized cannabis, using a commercially available vaporizing device, compared with an inert control substance and found no difference in either exertional dyspnea intensity or unpleasantness related to dyspnea in patients with COPD (n = 16).94 Although the findings of this randomized crossover design were negative, an editorial suggests that the dosage might have been insufficient, bronchodilator medications might have blunted the effect of cannabis, or the effect might have been minimized because of participant characteristics-most had hyperinflation and stopped exercise because of leg fatigue rather than dyspnea.95

 

Heliox

Only 1 study was found in our search that explored the use of Heliox, a mixture of helium and oxygen, but the results were very promising. In an RCT, patients who received Heliox experienced improved dyspnea and improved SaO2 and were able to walk farther than with either medical air or oxygen-enriched air.96 Given the sample size of n = 12, more research needs to be conducted to confirm the effectiveness. Heliox is not readily available outside of the critical care setting.

 

Oral Steroids

A Cochrane review of systemic corticosteroids for the management of dyspnea intensity, quality, and impact in patients with cancer identified 2 RCTs that compared dexamethasone to placebo (n = 114) for at least 1 week.97 The studies indicate lower dyspnea intensity compared with placebo at 1 week for those in the intervention compared with control group, but results for quality and impact were unclear because of imprecision, inconsistency, and study limitations. The authors point out the necessity of high-quality RCTs to answer this question; in the meantime, the available evidence does not either support or reject the value of systemic corticosteroids for the treatment of dyspnea in cancer.

 

Mindfulness Training

Although anecdotal reports from patients are passionate in favor of mindfulness-based stress reduction (MBSR), the only RCT of MBSR documented no improvement in dyspnea either with activity or at rest.98 A study of telephone-based mindfulness-focused acceptance and commitment therapy for patients with advanced cancer and caregivers showed similar results.99 Given that negative adverse effects are unlikely, a trial of MBSR may be considered on an individual basis.

 

Music Therapy

Early evidence from 2 nonrandomized studies suggests that music therapy reduces dyspnea and other symptoms. Statistically significant improvement in dyspnea has been documented in patients with multiple diagnoses on palliative care units who experienced live flute music selected by the patient.100 Dyspnea improvements were also demonstrated in the same population of patients who participated in a variety of music therapy activities.101

 

EFFECTIVENESS UNLIKELY

Nebulized Morphine and Epidural Methadone

Several studies including a recent systematic review have found a lack of effect of nebulized morphine18,102-105 to reduce dyspnea. Samples included patients with advanced cancers and COPD. Thus, we conclude that nebulized morphine is unlikely to be effective in alleviating dyspnea. A pilot study testing the safety of epidural methadone106 for patients (n = 6) diagnosed with advanced emphysema demonstrated clinical improvement in dyspnea. The small sample size prohibited detection of statistically significant improvement. In the absence of a full randomized trial, this evidence is too weak to support the effectiveness of epidural methadone.

 

Oxygen Without Hypoxemia and Near Death

Palliative oxygen versus medical air was tested in a multinational RCT of patients with life-limiting illness, refractory dyspnea, and no hypoxemia. No differences in dyspnea were found.107 Similarly, among a sample of patients who were near death and in no respiratory distress, oxygen was withdrawn with no change in respiratory comfort.108

 

WEAK EVIDENCE

Extended-Release Morphine for Pulmonary Arterial Hypertension

A single, randomized controlled, double-blind, placebo-controlled crossover trial of extended-release morphine for pulmonary arterial hypertension was done. The findings favored placebo for beneficial effects on dyspnea, and morphine generated more harm including nausea and constipation.109 Extended-release morphine is not indicated for dyspnea relief in patients with pulmonary arterial hypertension.

 

Oxycodone for Chronic Breathlessness

A multisite, randomized, placebo-controlled clinical trial of oral controlled-release oxycodone (5 mg every 8 hours) was conducted in patients with chronic breathlessness.110 The results found no difference in the rating of breathlessness intensity compared with placebo; therefore, oxycodone is not recommended.

 

Opioids to Improve Exercise Capacity

A systematic review conducted on the effect of opioids (varying formulations and doses) on breathlessness and exercise capacity in patients with COPD demonstrated a reduction in breathlessness but no improvement in exercise capacity.111

 

DISCUSSION

The evidence specific to dyspnea relief is very limited for the majority of interventions commonly used to manage dyspnea. Consequently, clinicians often use anecdotal evidence or interventions shown to improve the mechanisms of disease when recommending dyspnea relief interventions for their patients. Effective dyspnea relief is dependent on self-management and complementary interventions. Of the interventions most likely to be effective for dyspnea relief, only morphine, oxygen, inhalers, and interprofessional programs such as pulmonary rehabilitation and breathlessness interventions services are prescribed by a provider. Other interventions such as fans, breathing strategies, and acupressure can be accessed independently by patients and caregivers; however, education about these interventions is usually offered by a clinician.

 

Among pharmacological treatments, oral morphine is effective and safe in reducing acute episodic and chronic refractory dyspnea for patients with advanced lung diseases including COPD and lung cancer and in patients with heart failure. Clinical guidelines recommend beginning morphine at low doses for patients who are opioid-naive and titrating to achieve a balance of benefit with few adverse effects. Starting dose of immediate release morphine is 5 mg every 4 hours up to 30 mg/d and for SR 15 mg twice daily up to 30 mg/d. Common adverse effects include constipation, drowsiness, nausea, and vomiting. Bowel regimens should be routinely ordered to prevent constipation. Nebulized morphine is not effective in alleviating dyspnea. Patients and clinicians may be hesitant to initiate trials of morphine because of its addictive properties and potential to induce respiratory distress. Explaining the difference in dosing compared with pain management and studies reporting the lack of evidence of respiratory depression may mitigate concerns.

 

Oxygen use is a topic that stimulates much interest among hospice and palliative nurses and patients. The evidence supports the use of oxygen for dyspnea relief in patients who are hypoxic, but patients who are not hypoxic seem to experience as much dyspnea relief from medical air by nasal cannula as from supplemental oxygen. High-flow oxygen may provide some dyspnea relief, but the availability in the home setting is limited, and the benefit must be balanced with the potential discomfort of skin irritation, nasal dryness, gastric distension, or epistaxis. The effectiveness of Heliox has not been established, and it is not readily available outside of the critical care setting. Together, these findings suggest that oxygen may provide dyspnea relief in specific situations, but the goals of treatment and the patient's personal priorities are important considerations when deciding whether to include oxygen in the plan of care.

 

Pulmonary rehabilitation and exercise-based interventions have the strongest evidence within the category of nonpharmacologic dyspnea relief. The evidence is consistent and paradoxical-exercise training causes short-term increases in dyspnea, but if a person can cope with the dyspnea and continue exercise training over time, their physical fitness increases, they become less deconditioned, their functional reserves increase in respect to their daily activities, and their experience of dyspnea decreases in relationship to their usual daily activities.112 In addition, the fear and distress related to dyspnea-their "affective response" to the symptom decreases, possibly through desensitization.113 The positive effect of exercise on dyspnea has been demonstrated in formal pulmonary rehabilitation programs and also in-home exercise and holistic breathlessness interventions.

 

Given the unrelenting distress caused by dyspnea for people with serious and chronic illnesses, patients often search beyond traditional medical care for symptom relief. Interventions focused on acupoints, breathing strategies, music, and mindfulness all have enthusiastic anecdotal support, but the studies tend to be underpowered or nonexistent. These interventions are unlikely to cause serious adverse effects or complications, so "n of 1" trials while monitoring the patients for any potential unforeseen negative consequences make sense.8 Nutritional supplementation and nebulized cannabis are topics that deserve additional exploration. A 2012 volume on integrative therapies for people with lung disease provides additional exploration of nonpharmacologic therapies that may benefit patients with dyspnea.114

 

Many of the studies of nonpharmacologic interventions for dyspnea are limited by very small sample sizes. The lack of evidence in support of some dyspnea interventions may indicate that the research has not been done, rather than ineffectiveness an intervention. Given the dearth of effective evidence-based interventions for dyspnea, patients often find the most benefit by joining online or in-person support groups such as the American Lung Association's Better Breathers groups or EFFORTS (emphysema.net) and share strategies with each other that they find to be effective.

 

Music therapy is a benign intervention that lacks a strong evidence base. A number of rigorous trials have found effectiveness about music for pain relief; music may have a role for treating other symptoms such as dyspnea.115 A well-designed study on the effect of music on anxiety in ventilated critically ill patients could serve as a model for studying the effect of music on dyspnea.116

 

Application to Nursing Practice

Dyspnea is a debilitating symptom for patients and their caregivers and can escalate near the end of life. Acute episodes of "dyspnea crisis" are defined as a "sustained and severe resting breathing discomfort that occurs in patients with advanced, often life-limiting illness and overwhelms the patient and caregivers' ability to achieve symptom relief."117 Dyspnea crisis may result in overutilization of health care resources and requires individual and system-based approaches directed at prevention and early management. The American Thoracic Society statement provides an approach using a mnemonic "COMFORT" that can be adapted by patients and caregivers and practiced in advance, to minimize the panic of managing a dyspnea crisis118 (Figure 2).

  
Figure 2 - Click to enlarge in new windowFIGURE 2. Customizable caregiver plan for episodes of crisis dyspnea. Used with permission from the American Thoracic Society (August 12, 2020).

Limitations

The level of evidence available for many studies of dyspnea interventions is limited by sample size. The effect of disease mechanisms versus the common pathway of dyspnea sensation has not been delineated.119 Interventions may be specific to diagnoses, and others may affect the common pathway of dyspnea. Some intervention studies with dyspnea as the outcome of interest may have been missed by our search strategy. Many dyspnea interventions have only been tested in limited samples, often patients with COPD and cancer. Gaps remain regarding the effectiveness of many interventions in other diagnoses and populations. Interventions need to be tested over time in multiple dyspnea-causing diagnoses across the continuum of illness.

 

CONCLUSION

Dyspnea causes severe distress in patients with advanced stage illness. Our understanding of interventions to relieve dyspnea lags behind our understanding of dyspnea mechanisms and interventions for other symptoms such as pain. Recent developments in dyspnea measurement facilitate quantification of multidimensional dyspnea experience with very little patient or provider burden. Recognition of the value of dyspnea-specific interventions and addition of dyspnea measurement in studies of palliative and cardiopulmonary interventions would enhance the knowledge base for treating this distressing symptom.

 

Acknowledgment

The authors appreciate the expertise of members of the HPNA taskforce who served as reviewers: Elizabeth Fahlberg, Deborah Thorpe, and A. Walsh.

 

References

 

1. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185(4):435-452. [Context Link]

 

2. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage. 2006;31(1):58-69. [Context Link]

 

3. Currow DC, Smith J, Davidson PM, Newton PJ, Agar MR, Abernethy AP. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. J Pain Symptom Manage. 2010;39(4):680-690. [Context Link]

 

4. Campbell ML, Kiernan JM, Strandmark J, Yarandi HN. Trajectory of dyspnea and respiratory distress among patients in the last month of life. J Palliat Med. 2018;21(2):194-199. [Context Link]

 

5. Hui D, Bohlke K, Bao T, et al. Management of dyspnea in advanced cancer [epub ahead of print]. J Clin Oncol. [Context Link]

 

6. Mahler DA, Selecky PA, Harrod CG, et al. American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. Chest. 2010;137(3):674-691. [Context Link]

 

7. Marciniuk DD, Goodridge D, Hernandez P, et al. Managing dyspnea in patients with advanced chronic obstructive pulmonary disease: a Canadian thoracic society clinical practice guideline. Can Respir J. 2011;18(2):69-78. [Context Link]

 

8. Mirza RD, Punja S, Vohra S, Guyatt G. The history and development of N-of-1 trials. J R Soc Med. 2017;110(8):330-340. [Context Link]

 

9. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006-1012. [Context Link]

 

10. Oncology Nursing Society. Decision rules for summative evaluation of a body of evidence. 2019; http://www.ons.org/explore-resources/pep/decision-rules-summative-evaluation-bod. Accessed January 14, 2019. [Context Link]

 

11. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;57(11):939-944. [Context Link]

 

12. Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis. Acta Oncol. 2012;51(8):996-1008. [Context Link]

 

13. Allard P, Lamontagne C, Bernard P, Tremblay C. How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial. J Pain Symptom Manage. 1999;17(4):256-265. [Context Link]

 

14. Oxberry SG, Torgerson DJ, Bland JM, Clark AL, Cleland JG, Johnson MJ. Short-term opioids for breathlessness in stable chronic heart failure: a randomized controlled trial. Eur J Heart Fail. 2011;13(9):1006-1012. [Context Link]

 

15. American Thoracic Society. Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med. 1999;159(1):321-340. [Context Link]

 

16. Banzett RB, Adams L, O'Donnell CR, Gilman SA, Lansing RW, Schwartzstein RM. Using laboratory models to test treatment: morphine reduces dyspnea and hypercapnic ventilatory response. Am J Respir Crit Care Med. 2011;184(8):920-927. [Context Link]

 

17. Pattinson KTS, Governo RJ, MacIntosh BJ, et al. Opioids depress cortical centers responsible for the volitional control of respiration. 2009;29:8177-8186. [Context Link]

 

18. Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst Rev. 2016;3:CD011008. [Context Link]

 

19. Thomas JR, von Gunten CF. Clinical management of dyspnoea. Lancet Oncol. 2002;3(4):223-228. [Context Link]

 

20. West JB. Respiratory Physiology: The Essentials. Philadelphia, PA: Lippincott, Williams and Wilkins; 1999. [Context Link]

 

21. Uronis H, McCrory DC, Samsa G, Currow D, Abernethy A. Symptomatic oxygen for non-hypoxaemic chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;6:CD006429. [Context Link]

 

22. Jacobs SS, Krishnan JA, Lederer DJ, et alAmerican Thoracic Society. Home oxygen therapy for adults with COPD and ILD: new ATS clinical practice guideline. Am J Respir Crit Care Med. 2020;202. https://doi.org/10.1164/rccm.202009-3608ST. [Context Link]

 

23. Swan F, Booth S. The role of airflow for the relief of chronic refractory breathlessness. Curr Opin Support Palliat Care. 2015;9(3):206-211. [Context Link]

 

24. Schwartzstein RM, Lahive K, Pope A, Weinberger SE, Weiss JW. Cold facial stimulation reduces breathlessness induced in normal subjects. Am Rev Respir Dis. 1987;136:58-61. [Context Link]

 

25. Bausewein C, Booth S, Gysels M, Kuhnbach R, Higginson IJ. Effectiveness of a hand-held fan for breathlessness: a randomised phase II trial. BMC Palliat Care. 2010;9:22. [Context Link]

 

26. Galbraith S, Fagan P, Perkins P, Lynch A, Booth S. Does the use of a hand-held fan improve chronic dyspnea: a randomized, controlled, crossover trial. J Pain Symptom Manage. 2010;39(5):831-838. [Context Link]

 

27. Luckett T, Phillips J, Johnson MJ, et al. Contributions of a hand-held fan to self-management of chronic breathlessness. Eur Respir J. 2017;50(2). [Context Link]

 

28. Kako J, Morita T, Yamaguchi T, et al. Fan therapy is effective in relieving dyspnea in patients with terminally ill cancer: a parallel-arm, randomized controlled Trial. J Pain Symptom Manage. 2018;56(4):493-500. [Context Link]

 

29. Yu S, Sun K, Xing X, et al. Fan therapy for the relief of dyspnea in adults with advanced disease and terminal illness: a meta-analysis of randomized controlled trials. J Palliat Med. 2019;22(12):1603-1609. [Context Link]

 

30. Nici L, Mammen MJ, Charbek E, et alAmerican Thoracic Society. Pharmacologic management of chronic obstructive pulmonary disease: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e-56-69. [Context Link]

 

31. Gotfried MH, Kerwin EM, Lawrence D, Lassen C, Kramer B. Efficacy of indacaterol 75 mug once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies. COPD. 2012;9(6):629-636. [Context Link]

 

32. Mahler DA, Decramer M, D'Urzo A, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014;43(6):1599-1609. [Context Link]

 

33. Mahler DA, D'Urzo A, Bateman ED, et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax. 2012;67(9):781-788. [Context Link]

 

34. Sansores R, Ramirez-Vanegas A, Reddy C, Mejia-Alfaro R. Effect of the combination of two bronchodilators on breathlessness in patients with chronic obstructive pulmonary disease. A crossover clinical trial. Arch Med Res. 2003;34(4):292-297. [Context Link]

 

35. Tashkin DP, Donohue JF, Mahler DA, et al. Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD. Respir Med. 2009;103(4):516-524. [Context Link]

 

36. Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014;(10):Cd006322. [Context Link]

 

37. Wadell K, Webb KA, Preston ME, et al. Impact of pulmonary rehabilitation on the major dimensions of dyspnea in COPD. COPD. 2013;10(4):425-435. [Context Link]

 

38. Chen YJ, Li XX, Ma HK, et al. Exercise training for improving patient-reported outcomes in patients with advanced-stage cancer: a systematic review and meta-analysis. J Pain Symptom Manage. 2019. [Context Link]

 

39. Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327(7414):523-528. [Context Link]

 

40. Johnson MJ, Sbizzera I, Fairhurst C, et al. No excess harms from sustained-release morphine: a randomised placebo-controlled trial in chronic breathlessness. BMJ Support Palliat Care. 2019. [Context Link]

 

41. Currow DC, Quinn S, Greene A, Bull J, Johnson MJ, Abernethy AP. The longitudinal pattern of response when morphine is used to treat chronic refractory dyspnea. J Palliat Med. 2013;16(8):881-886. [Context Link]

 

42. Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind controlled trial. Ann Oncol. 1999;10(12):1511-1514. [Context Link]

 

43. Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol. 2008;26(14):2396-2404. [Context Link]

 

44. Verberkt CA, van den Beuken-van Everdingen MHJ, Schols J, et al. Respiratory adverse effects of opioids for breathlessness: a systematic review and meta-analysis. Eur Respir J. 2017;50(5):1701153. [Context Link]

 

45. Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for Chronic Obstructive Lung Disease global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2018. http://www.goldcopd.org. Accessed May 31, 2018. [Context Link]

 

46. Vitacca M, Scalvini S, Volterrani M, Paneroni M, Giordano A, Ambrosino N. Physiological and symptom effects of changing posture from sitting to supine, and vice versa, in stable chronic heart failure. Acta Cardiol. 2016;71(5):543-548. [Context Link]

 

47. Johnson MJ, Kanaan M, Richardson G, et al. A randomised controlled trial of three or one breathing technique training sessions for breathlessness in people with malignant lung disease. BMC Med. 2015;13:213. [Context Link]

 

48. Hoffman M, Augusto VM, Eduardo DS, Silveira BMF, Lemos MD, Parreira VF. Inspiratory muscle training reduces dyspnea during activities of daily living and improves inspiratory muscle function and quality of life in patients with advanced lung disease. Physiother Theory Pract. 2019;1-11. [Context Link]

 

49. Carrieri-Kohlman V, Nguyen HQ, Donesky-Cuenco D, Demir-Deviren S, Neuhaus J, Stulbarg MS. Impact of brief or extended exercise training on the benefit of a dyspnea self-management program in COPD. J Cardiopulm Rehabil. 2005;25(5):275-284. [Context Link]

 

50. Nguyen HQ, Donesky D, Reinke LF, et al. Internet-based dyspnea self-management support for patients with chronic obstructive pulmonary disease. J Pain Symptom Manage. 2013;46(1):43-55. [Context Link]

 

51. Nguyen HQ, Donesky-Cuenco D, Wolpin S, et al. Randomized controlled trial of an internet-based versus face-to-face dyspnea self-management program for patients with chronic obstructive pulmonary disease: pilot study. J Med Internet Res. 2008;10(2):e9. [Context Link]

 

52. Wakabayashi R, Kusunoki Y, Hattori K, et al. Effectiveness of home-based exercise in older patients with advanced chronic obstructive pulmonary disease: a 3-year cohort study. Geriatr Gerontol Int. 2018;18(1):42-49. [Context Link]

 

53. Corner J, Plant H, A'Hern R, Bailey C. Non-pharmacological intervention for breathlessness in lung cancer. Palliat Med. 1996;10(4):299-305. [Context Link]

 

54. Farquhar MC, Prevost AT, McCrone P, et al. Is a specialist breathlessness service more effective and cost-effective for patients with advanced cancer and their carers than standard care? Findings of a mixed-method randomised controlled trial. BMC Med. 2014;12:194. [Context Link]

 

55. Higginson IJ, Bausewein C, Reilly CC, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial. Lancet Respir Med. 2014;2(12):979-987. [Context Link]

 

56. Qian MYY, Politis J, Thompson M, et al. Individualized breathlessness interventions may improve outcomes in patients with advanced COPD. Respirology (Carlton, Vic). 2018;23(12):1146-1151. [Context Link]

 

57. Elbehairy AF, McIsaac H, Hill E, et al. Impact of a specialized ambulatory clinic on refractory breathlessness in subjects with advanced COPD: a retrospective analysis. Respir Care. 2019. [Context Link]

 

58. Brighton LJ, Miller S, Farquhar M, et al. Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis. Thorax. 2019;74(3):270-281. [Context Link]

 

59. Lau KS, Jones AY. A single session of Acu-TENS increases FEV1 and reduces dyspnoea in patients with chronic obstructive pulmonary disease: a randomised, placebo-controlled trial. Aust J Physiother. 2008;54(3):179-184. [Context Link]

 

60. Wu HS, Wu SC, Lin JG, Lin LC. Effectiveness of acupressure in improving dyspnoea in chronic obstructive pulmonary disease. J Adv Nurs. 2004;45(3):252-259. [Context Link]

 

61. Nava S, Ferrer M, Esquinas A, et al. Palliative use of non-invasive ventilation in end-of-life patients with solid tumours: a randomised feasibility trial. Lancet Oncol. 2013;14(3):219-227. [Context Link]

 

62. Curtis JR, Cook DJ, Sinuff T, et al. Noninvasive positive pressure ventilation in critical and palliative care settings: understanding the goals of therapy. Crit Care Med. 2007;35:932-939. [Context Link]

 

63. Hui D, Morgado M, Chisholm G, et al. High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized Trial. J Pain Symptom Manage. 2013;46(4):463-473. [Context Link]

 

64. Ruangsomboon O, Dorongthom T, Chakorn T, et al. High-flow nasal cannula versus conventional oxygen therapy in relieving dyspnea in emergency palliative patients with do-not-intubate status: a randomized crossover study. Ann Emerg Med. 2020;75(5):615-626. [Context Link]

 

65. Zemach S, Helviz Y, Shitrit M, Friedman R, Levin PD. The use of high-flow nasal cannula oxygen outside the ICU. Respir Care. 2019;64(11):1333-1342. [Context Link]

 

66. Marinari S, Manigrasso MR, De Benedetto F. Effects of nutraceutical diet integration, with coenzyme Q10 (Q-Ter multicomposite) and creatine, on dyspnea, exercise tolerance, and quality of life in COPD patients with chronic respiratory failure. Multidiscip Respir Med. 2013;8(1):40. [Context Link]

 

67. Vickers AJ, Feinstein MB, Deng GE, Cassileth BR. Acupuncture for dyspnea in advanced cancer: a randomized, placebo-controlled pilot trial [ISRCTN89462491]. BMC Palliat Care. 2005;4:5. [Context Link]

 

68. Miller KR, Patel JN, Symanowski JT, Edelen CA, Walsh D. Acupuncture for cancer pain and symptom management in a palliative medicine clinic. Am J Hosp Palliat Care. 2019;36(4):326-332. [Context Link]

 

69. Romeo MJ, Parton B, Russo RA, Hays LS, Conboy L. Acupuncture to treat the symptoms of patients in a palliative care setting. Explore (NY). 2015;11(5):357-362. [Context Link]

 

70. Pandit A, Gupta N, Kumar V, et al. Effect of palliative bronchoscopic interventions on symptom burden in patients with central airway narrowing: a retrospective review. Indian J Palliat Care. 2019;25(2):250-253. [Context Link]

 

71. Dransfield MT, Garner JL, Bhatt SP, et al. Effect of Zephyr endobronchial valves on dyspnea, activity levels, and quality of life at one year. Results from a randomized clinical Trial. Ann Am Thorac Soc. 2020;17(7):829-838. [Context Link]

 

72. Ryerson CJ, Donesky D, Pantilat SZ, Collard HR. Dyspnea in idiopathic pulmonary fibrosis: a systematic review. J Pain Symptom Manage. 2012;43(4):771-782. [Context Link]

 

73. Eiser N, Denman WT, West C, Luce P. Oral diamorphine: lack of effect on dyspnoea and exercise tolerance in the "pink puffer" syndrome. Eur Respir J. 1991;4(8):926-931. [Context Link]

 

74. Coyne PJ, Viswanathan R, Smith TJ. Nebulized fentanyl citrate improves patients' perception of breathing, respiratory rate, and oxygen saturation in dyspnea. J Pain Symptom Manage. 2002;23(2):157-160. [Context Link]

 

75. Pinna MA, Bruera E, Moralo MJ, Correas MA, Vargas RM. A randomized crossover clinical trial to evaluate the efficacy of oral transmucosal fentanyl citrate in the treatment of dyspnea on exertion in patients with advanced cancer. Am J Hosp Palliat Care. 2015;32(3):298-304. [Context Link]

 

76. Jansen K, Haugen DF, Pont L, Ruths S. Safety and effectiveness of palliative drug treatment in the last days of life-a systematic literature review. J Pain Symptom Manage. 2018;55(2):508-521.e3. [Context Link]

 

77. Benitez-Rosario MA, Rosa-Gonzalez I, Gonzalez-Davila E, Sanz E. Fentanyl treatment for end-of-life dyspnoea relief in advanced cancer patients. Support Care Cancer. 2019;27(1):157-164. [Context Link]

 

78. Currow D, Louw S, McCloud P, et al. Regular, sustained-release morphine for chronic breathlessness: a multicentre, double-blind, randomised, placebo-controlled trial. Thorax. 2019;75(1):50-56. [Context Link]

 

79. Aabom B, Laier G, Christensen PL, Karlsson T, Jensen MB, Hedal B. Oral morphine drops for prompt relief of breathlessness in patients with advanced cancer-a randomized, double blinded, crossover trial of morphine sulfate oral drops vs. morphine hydrochloride drops with ethanol (red morphine drops). Support Care Cancer. 2019;28(7):3421-3428. [Context Link]

 

80. Kamell A, Smith LK. Attitudes toward use of benzodiazepines among U.S. hospice clinicians: survey and review of the literature. J Palliat Med. 2016;19(5):516-522. [Context Link]

 

81. Allcroft P, Margitanovic V, Greene A, et al. The role of benzodiazepines in breathlessness: a single site, open label pilot of sustained release morphine together with clonazepam. J Palliat Med. 2013;16(7):741-744. [Context Link]

 

82. Peoples AR, Bushunow PW, Garland SN, et al. Buspirone for management of dyspnea in cancer patients receiving chemotherapy: a randomized placebo-controlled URCC CCOP study. Support Care Cancer. 2016;24(3):1339-1347. [Context Link]

 

83. Simon ST, Higginson IJ, Booth S, Harding R, Weingartner V, Bausewein C. Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults. Cochrane Database Syst Rev. 2016;10:CD007354. [Context Link]

 

84. Navigante AH, Cerchietti LC, Castro MA, Lutteral MA, Cabalar ME. Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage. 2006;31(1):38-47. [Context Link]

 

85. Booth S, Kelly MJ, Cox NP, Adams L, Guz A. Does oxygen help dyspnea in patients with cancer?Am J Respir Crit Care Med. 1996;153(5):1515-1518. [Context Link]

 

86. Bruera E, de Stoutz N, Velasco-Leiva A, Schoeller T, Hanson J. Effects of oxygen on dyspnoea in hypoxaemic terminal-cancer patients. Lancet. 1993;342:13-14. [Context Link]

 

87. Philip J, Gold M, Milner A, Di Iulio J, Miller B, Spruyt O. A randomized, double-blind, crossover trial of the effect of oxygen on dyspnea in patients with advanced cancer. J Pain Symptom Manage. 2006;32(6):541-550. [Context Link]

 

88. Sepehrvand N, Alemayehu W, Rowe BH, et al. High vs. low oxygen therapy in patients with acute heart failure: HiLo-HF pilot trial. ESC Heart Fail. 2019;6(4):667-677. [Context Link]

 

89. Albert RK, Au DH, et alLong-term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375(17):1617-1627. [Context Link]

 

90. Kohara H, Ueoka H, Aoe K, et al. Effect of nebulized furosemide in terminally ill cancer patients with dyspnea. J Pain Symptom Manage. 2003;26(4):962-967. [Context Link]

 

91. Shimoyama N, Shimoyama M. Nebulized furosemide as a novel treatment for dyspnea in terminal cancer patients. J Pain Symptom Manage. 2002;23(1):73-76. [Context Link]

 

92. Wilcock A, Walton A, Manderson C, et al. Randomised, placebo controlled trial of nebulised furosemide for breathlessness in patients with cancer. Thorax. 2008;63(10):872-875. [Context Link]

 

93. Morelot-Panzini C, O'Donnell CR, Lansing RW, Schwartzstein RM, Banzett RB. Aerosol furosemide for dyspnea: controlled delivery does not improve effectiveness. Respir Physiol Neurobiol. 2018;247:146-155. [Context Link]

 

94. Abdallah SJ, Smith BM, Ware MA, et al. Effect of vaporized cannabis on exertional breathlessness and exercise endurance in advanced chronic obstructive pulmonary disease. A randomized controlled Trial. Ann Am Thorac Soc. 2018;15(10):1146-1158. [Context Link]

 

95. Tashkin DP. Vaping cannabis and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2018;15(10):1137-1138. [Context Link]

 

96. Ahmedzai SH, Laude E, Robertson A, Troy G, Vora V. A double-blind, randomised, controlled phase II trial of Heliox28 gas mixture in lung cancer patients with dyspnoea on exertion. Br J Cancer. 2004;90(2):366-371. [Context Link]

 

97. Haywood A, Duc J, Good P, et al. Systemic corticosteroids for the management of cancer-related breathlessness (dyspnoea) in adults. Cochrane Database Syst Rev. 2019;2: Cd012704. [Context Link]

 

98. Mularski RA, Munjas BA, Lorenz KA, et al. Randomized controlled trial of mindfulness-based therapy for dyspnea in chronic obstructive lung disease. J Altern Complement Med. 2009;15(10):1083-1090. [Context Link]

 

99. Mosher CE, Secinti E, Hirsh AT, et al. Acceptance and commitment therapy for symptom interference in advanced lung cancer and caregiver distress: a pilot randomized trial. J Pain Symptom Manage. 2019;58(4):632-644. [Context Link]

 

100. Peng CS, Baxter K, Lally KM. Music intervention as a tool in improving patient experience in palliative care. Am J Hosp Palliat Care. 2019;36(1):45-49. [Context Link]

 

101. Gallagher LM, Lagman R, Rybicki L. Outcomes of music therapy interventions on symptom management in palliative medicine patients. Am J Hosp Palliat Care. 2018;35(2):250-257. [Context Link]

 

102. Noseda A, Carpiaux JP, Markstein C, Meyvaert A, de Maertelaer V. Disabling dyspnoea in patients with advanced disease: lack of effect of nebulized morphine. Eur Respir J. 1997;10(5):1079-1083. [Context Link]

 

103. Bruera E, Sala R, Spruyt O, Palmer JL, Zhang T, Willey J. Nebulized versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study. J Pain Symptom Manage. 2005;29(6):613-618. [Context Link]

 

104. Kallet RH. The role of inhaled opioids and furosemide for the treatment of dyspnea. Respir Care. 2007;52(7):900-910. [Context Link]

 

105. Masood AR, Reed JW, Thomas SH. Lack of effect of inhaled morphine on exercise-induced breathlessness in chronic obstructive pulmonary disease. Thorax. 1995;50(6):629-634. [Context Link]

 

106. Juan G, Ramon M, Valia JC, et al. Palliative treatment of dyspnea with epidural methadone in advanced emphysema. Chest. 2005;128(5):3322-3328. [Context Link]

 

107. Abernethy AP, McDonald CF, Frith PA, et al. Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet. 2010;376(9743):784-793. [Context Link]

 

108. Campbell ML, Yarandi H, Dove-Medows E. Oxygen is nonbeneficial for most patients who are near death. J Pain Symptom Manage. 2013;45(3):517-523. [Context Link]

 

109. Ferreira DH, Ekstrom M, Sajkov D, Vandersman Z, Eckert DJ, Currow DC. Extended-release morphine for chronic breathlessness in pulmonary arterial hypertension-a randomized, double-blind, placebo-controlled, crossover study. J Pain Symptom Manage. 2018;56(4):483-492. [Context Link]

 

110. Ferreira DH, Louw S, McCloud P, et al. Controlled-release oxycodone versus placebo in the treatment of chronic breathlessness-a multi-site randomised placebo controlled trial. J Pain Symptom Manage. 2019. [Context Link]

 

111. Ekstrom M, Nilsson F, Abernethy AA, Currow DC. Effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease. A systematic review. Ann Am Thorac Soc. 2015;12(7):1079-1092. [Context Link]

 

112. O'Donnell DE, James MD, Milne KM, Neder JA. The pathophysiology of dyspnea and exercise intolerance in chronic obstructive pulmonary disease. Clin Chest Med. 2019;40(2):343-366. [Context Link]

 

113. Donesky D, Nguyen HQ, Paul SM, Carrieri-Kohlman V. The affective dimension of dyspnea improves in a dyspnea self-management program with exercise training. J Pain Symptom Manage. 2014;47(4):757-771. [Context Link]

 

114. Chlan L, Hertz MI. Integrative Therapies in Lung Health and Sleep. New York: Humana; 2012. [Context Link]

 

115. Cepeda MS, Carr DB, Lau J, Alvarez H. Music for pain relief. Cochrane Database Syst Rev. 2006;2. [Context Link]

 

116. Chlan LL, Weinert CR, Heiderscheit A, et al. Effects of patient-directed music intervention on anxiety and sedative exposure in critically ill patients receiving mechanical ventilatory support: a randomized clinical trial. JAMA. 2013;309(22):2335-2344. [Context Link]

 

117. Mularski RA, Reinke LF, Carrieri-Kohlman V, et al. An official American Thoracic Society workshop report: assessment and palliative management of dyspnea crisis. Ann Am Thorac Soc. 2013;10(5):S98-S106. [Context Link]

 

118. Schneidman A, Reinke L, Donesky D, Carrieri-Kohlman V. Patient information series. Sudden breathlessness crisis. Am J Respir Crit Care Med. 2014;189(5):P9-P10. [Context Link]

 

119. Booth S, Johnson MJ. Improving the quality of life of people with advanced respiratory disease and severe breathlessness. Breathe (Sheff). 2019;15(3):198-215. [Context Link]