Chronic Refractory Breathlessness Research Articles

Management of Refractory Breathlessness: a Review for General Internists.

Internists frequently care for patients who suffer from breathlessness in both the inpatient and the outpatient settings. Patients may experience chronic refractory breathlessness despite thorough evaluation and management of their underlying medical illnesses. Left unmanaged, chronic breathlessness is associated with worsened quality of life, more frequent visits to the emergency room, and decreased activity levels, as well as increased levels of depression and anxiety. This narrative review summarizes recent research on interventions for the relief of breathlessness, including both non-pharmacologic and pharmacologic options.

What Constitutes Good Health Care for Patients with Breathlessness? Perspectives of Patients, Caregivers, and Health Care Professionals.

Background/Objective: Breathlessness is a highly prevalent and distressing symptom in patients with cancer and advanced chronic diseases. Symptom management is often overlooked. We explored the experiences of patients, caregivers, and health care providers (HCPs) and their expectations for future service developments. Design: This is a multiperspective qualitative study drawing on semistructured interviews. Setting/Subjects: Participants were recruited from palliative, respiratory, and cardiology departments of the Munich University Hospital and from a chronic obstructive pulmonary disease (COPD) patient group. Measurements: Interviews were analyzed using qualitative content analysis. Subcategories used the directional views of participants (positive, negative, and indifferent). The coding tree identified three categories: (1) attributes of symptom management, (2) practice pattern gaps, and (3) components of good practice. Results: Ten patients (5 female, 65.2 median age; COPD n = 3, cancer n = 3, chronic heart failure n = 2, and lung fibrosis n = 2), 3 caregivers (2 female, 53.6 median age), and 10 HCPs were interviewed. Patients and caregivers felt stressed and frustrated due to a lack of awareness regarding the symptom burden and little support from HCPs. HCPs pointed to a lack of therapeutic concepts and unclear assumptions of responsibilities. Specialist breathlessness services are perceived as addressing important gaps in professional practice from the viewpoint of all stakeholders. Accessibility and collaboration with other local health care services are important features of such specialist services. Conclusions: Chronic refractory breathlessness in advanced disease is managed insufficiently for most patients, caregivers, and HCPs. Increased knowledge about effective interventions and availability of skills-based training for patients, caregivers, and HCPs would help in breathlessness management.

Managing chronic breathlessness in the community.

Breathlessness or dyspnoea is a subjective experience that can be described as an unpleasant or uncomfortable awareness of breathing. It is a subjective experience for patients and often they learn to adapt to the limitations caused by their condition, which makes their breathlessness less apparent to others. Breathlessness can be subdivided in the context of chronic refractory breathlessness, such as acute breathlessness, which is either an episodic breathlessness or breathlessness crisis. Chronic refractory breathlessness is defined as breathlessness at rest or on minimal exertion that will persist chronically despite optimal treatment of the underlying causative factors. The role of the community nurse in managing the breathless patient should involve differentiating between different types of breathlessness and knowing how to effectively manage it in a holistic manner.

Variations in the cost of formal and informal health care for patients with advanced chronic disease and refractory breathlessness: A cross-sectional secondary analysis

Background: Refractory breathlessness in advanced chronic disease leads to high levels of disability, anxiety and social isolation. These result in high health-resource use, although this is not quantified. Aims: To measure the cost of care for patients with advanced disease and refractory breathlessness and to identify factors associated with high costs. Design: A cross-sectional secondary analysis of data from a randomised controlled trial. Setting/participants: Patients with advanced chronic disease and refractory breathlessness recruited from three National Health Service hospitals and via general practitioners in South London. Results: Of 105 patients recruited, the mean cost of formal care was £3253 (standard deviation £3652) for 3 months. The largest contributions to formal-care cost were hospital admissions (>60%), and palliative care contributed <1%. When informal care was included, the total cost increased by >250% to £11,507 (standard deviation £9911). Increased patient disability resulting from breathlessness was associated with high cost (£629 per unit increase in disability score; p = 0.006). Increased breathlessness on exertion and the presence of an informal carer were also significantly associated with high cost. Patients with chronic obstructive pulmonary disease tended to have higher healthcare costs than other patients. Conclusion: Informal carers contribute significantly to the care of patients with advanced disease and refractory breathlessness. Disability resulting from breathlessness is an important clinical cost driver. It is important for policy makers to support and acknowledge the contributions of informal carers. Further research is required to assess the clinical- and cost-effectiveness of palliative care interventions in reducing disability resulting from breathlessness in this patient group.

A Mixed-Methods, Randomized, Controlled Feasibility Trial to Inform the Design of a Phase III Trial to Test the Effect of the Handheld Fan on Physical Activity and Carer Anxiety in Patients With Refractory Breathlessness

ContextThe handheld fan is an inexpensive and safe way to provide facial airflow, which may reduce the sensation of chronic refractory breathlessness, a frequently encountered symptom. ObjectivesTo test the feasibility of developing an adequately powered, multicenter, multinational randomized controlled trial comparing the efficacy of a handheld fan and exercise advice with advice alone in increasing activity in people with chronic refractory breathlessness from a variety of medical conditions, measuring recruitment rates; data quality; and potential primary outcome measures. MethodsThis was a Phase II, multisite, international, parallel, nonblinded, mixed-methods randomized controlled trial. Participants were centrally randomized to fan or control. All received breathlessness self-management/exercise advice and were followed up weekly for four weeks. Participants/carers were invited to participate in a semistructured interview at the study's conclusion. ResultsNinety-seven people were screened, 49 randomized (mean age 68 years; 49% men), and 43 completed the study. Site recruitment varied from 0.25 to 3.3/month and screening:randomization from 1.1:1 to 8.5:1. There were few missing data except for the Chronic Obstructive Pulmonary Disease Self-Efficacy Scale (two-thirds of data missing). No harms were observed. Three interview themes included 1) a fan is a helpful self-management strategy, 2) a fan aids recovery, and 3) a symptom control trial was welcome. ConclusionA definitive, multisite trial to study the use of the handheld fan as part of self-management of chronic refractory breathlessness is feasible. Participants found the fan useful. However, the value of information for changing practice or policy is unlikely to justify the expense of such a trial, given perceived benefits, the minimal costs, and an absence of harms demonstrated in this study.

Effects of low-dose morphine on perceived sleep quality in patients with refractory breathlessness: A hypothesis generating study.

The management of chronic refractory breathlessness is one of the indications for regular low-dose (≤30 mg/24 h) oral sustained release morphine. Morphine may disrupt sleep in some conditions and improve sleep quality in others. This study aimed to determine any signal of regular, low-dose morphine on perceived sleep disruption due to breathlessness and perceived sleep quality. This is a secondary analysis of data from 38 participants with refractory breathlessness (30 male; 33 with COPD) aged 76 ± 0.9 years who completed a double-blind, randomized, placebo-controlled, cross-over study in which they received 20 mg oral sustained release morphine daily and placebo for 4 days each. Participant ratings of sleep disruption due to breathlessness and perceived sleep quality were obtained daily throughout the 8-day trial. Perceived sleep disruption due to breathlessness over the 4-day period ranged between 13% and 32% of participants for placebo and 13% and 26% for morphine, decreasing by each day of the study during the morphine arm. Most participants reported 'very good' or 'quite good' sleep throughout the trial and were less likely to perceive poor sleep quality during the morphine arm (odds ratio = 0.55, 95% confidence interval: 0.34-0.88, P = 0.01). Participants who reported decreased breathlessness during the 4 days on morphine were also likely to report improved sleep quality with morphine (P = 0.039). Four days of low-dose morphine improved perceived sleep quality in elderly participants with refractory breathlessness. Regular low-dose morphine targeted to reduce refractory breathlessness may yield associated benefits by reducing sleep disruption and improving sleep quality.

Blinded Patient Preference for Morphine Compared to Placebo in the Setting of Chronic Refractory Breathlessness—An Exploratory Study

ContextPatients' preference for morphine therapy has received little attention in the setting of chronic refractory breathlessness. However, this is one important factor in considering longer term therapy. ObjectivesThe aim of this secondary analysis was to explore blinded patient preference of morphine compared to placebo for this indication and to define any predictors of preference. MethodsData were pooled from three randomized, double-blind, crossover, placebo-controlled studies of morphine (four days each) in chronic refractory breathlessness. Blinded patient preferences were chosen at the end of each study. A multivariable regression model was used to establish patient predictors of preference. ResultsSixty-five participants provided sufficient data (60 men; median age 74 years; heart failure 55%, chronic obstructive pulmonary disease 45%; median Eastern Cooperative Oncology Group performance status 2). Forty-three percent of participants preferred morphine (32% placebo and 25% no preference). Morphine preference and younger age were strongly associated: odds ratio = 0.85, 95% confidence interval 0.78–0.93; P < 0.001). There was also an inverse association between morphine preference and sedation (odds ratio = 0.77, 95% confidence interval 0.60–0.99; P < 0.05). An inverse association was also seen between nausea and morphine preference in the univariate model only (P < 0.05). No association was seen between morphine preference and breathlessness intensity, either at baseline or change from baseline. ConclusionParticipants preferred morphine over placebo for the relief of chronic refractory breathlessness. Morphine offers clinically important improvement, but net benefit can be easily outweighed by side effects, reducing net benefits. Side effects require aggressive management to allow more patients to realize benefits.

The importance of the feasibility study: Lessons from a study of the hand-held fan used to relieve dyspnea in people who are breathless at rest

Background: The dyspnea accompanying advanced cardiorespiratory disease is often refractory to palliation. It is disabling, distressing and associated with the diseases most common everywhere in the world. The hand-held fan, used to generate a draught across the face, is a simple, cost-effective, safe, and universally applicable palliative breathlessness intervention, consistently described as valuable in qualitative research. A previous crossover trial confirmed its benefit in patients breathless at rest, but the washout period was uncertain. Aim: To determine the washout period after use of the hand-held fan to inform accurate randomized controlled trial design. Design: An observational methodological study. Breathlessness intensity was measured using 100 mm visual analog scale and numerical rating scale, and “relief of breathlessness” was measured on a 5-point scale. Those benefitting from the fan provided visual analog scale/numerical rating scale scores until (1) scores returned to baseline values or (2) until response had plateaued. The primary outcome measure was the time (in minutes) to reach either component of the primary study endpoint. Settings/participants: Four in-/out-patient hospice/hospital units; participants had chronic refractory breathlessness using the fan. Results: Overall, 31 patients participated (mean age: 74.8 years; range: 49–98 years, standard deviation = 11.5 years); 64% were males. Approximately, half of the sample experienced benefit of moderate effect size. The relative reduction in breathlessness relative to the mean baseline score for the sample was 27% for the visual analog scale and 19% for the numerical rating scale. Conclusion: Feasibility work is essential, even for simple widely employed interventions.

The role of airflow for the relief of chronic refractory breathlessness.

Chronic refractory breathlessness is a major cause of suffering to people with advanced stage cardiorespiratory and some neurodegenerative diseases. It is a frightening, distressing and disabling symptom that imposes significant burdens on family members. Evidence is mounting for the role of facial or nasal airflow for the relief of chronic refractory breathlessness in those patients with mild hypoxaemia or normoxaemia. Airflow can be delivered from a cylinder of compressed medical air via face mask or nasal cannulae or a hand-held fan. The hand-held fan offers patients a simple, low-cost, self-management strategy that is not associated with any known risks. Therefore, it is timely and relevant to review the research available for the efficacy and appropriateness of facial or nasal airflow. There is sufficient review evidence available to suggest that airflow from the hand-held fan or medical air can provide clinically relevant and discernible relief of chronic refractory breathlessness at rest in patients with advanced diseases. The hand-held fan should be considered as one of the first interventions to try in management plans for patients who present with mild hypoxaemia or normoxaemia and chronic refractory breathlessness at rest or on minimal exertion. Emerging evidence indicates that airflow from the hand-held fan may also have an important role with exertion-induced breathlessness, decreasing distress and speeding recovery time after exercise, thereby helping patients self-manage their symptoms during everyday general activity and plan for crises of breathlessness, secure in the knowledge that they have a tangible, easily portable device to try in any circumstances.

Management of acute breathlessness in the person with chronic refractory breathlessness.

The purpose of this review is to synthesize the current literature on classification and management of acute breathlessness that occurs in patients who are living with chronic refractory breathlessness related to cancer, cardiopulmonary, or neuromuscular disease. In the context of chronic refractory breathlessness, acute breathlessness can be classified as either episodic breathlessness or breathlessness crisis. Episodic breathlessness is characterized by the severity, duration, and predictability of the symptom, and by the presence or absence of a trigger such as exertion, emotion, or an environmental factor. Breathlessness crisis is more sustained, occurs at rest, and overwhelms the patient's and caregivers' coping abilities, similar to the nontriggered unpredictable types of episodic breathlessness. Treatment of acute breathlessness focuses on alleviating the episode as quickly as possible without escalating medical intervention that may not be consistent with the patient's treatment preferences. Attention to breathlessness in the published literature has increased exponentially in the past two decades. The challenge is now to translate the research findings into relief of symptoms, suffering, and distress in those who suffer from acute and chronic breathlessness because of chronic illness.

Outcome measurement of refractory breathlessness: endpoints and important differences.

Standardized measurement of self-rated breathlessness using appropriate tools is essential for research and clinical care. The purpose was to review recent advances in the measurement of breathlessness and the minimal clinically important differences (MCIDs) in intensity of chronic breathlessness. Two tools have been validated in people with chronic obstructive pulmonary disease (COPD) to measure daily symptoms and breathlessness related to daily activities. Two multidimensional tools have been developed for different settings and aetiologies, which measure both the perceived intensity, unpleasantness, quality of breathlessness, and the person's emotional response to it. MCIDs have been reported for the intensity of chronic refractory breathlessness, the daily symptom diary, and breathlessness related to daily activities in COPD. There have been substantial developments in instruments able to provide reliable and valid unidimensional and multidimensional measurement of self-reported breathlessness and in the understanding of the MCID for chronic breathlessness. Routine use of agreed outcome measures in clinical practice and research are crucial steps to improve our understanding of the science of breathlessness and its impact on patients' outcomes.

Consider opioid therapy for chronic refractory breathlessness

Treatment for chronic breathlessness should be considered only when management of the underlying disease has been fully optimized. Opioids are indicated as first-line therapy, as this is the only class of drugs that has demonstrated clear clinical benefits in patients with chronic refractory breathlessness. Oral and parenteral, but not nebulized, delivery of opioids has been shown to be effective. Data plainly indicating that benzodiazepines or oxygen have therapeutic benefits in treating this condition are currently lacking.

Opioids for Chronic Refractory Breathlessness: Right Patient, Right Route?

Chronic breathlessness at rest or on minimal exertion despite optimal treatment of the underlying chronic cause(s) is termed chronic refractory breathlessness. This is prevalent across the community and is an independent indicator of poor prognosis. This narrative review focuses on the palliation of chronic refractory breathlessness in people predominantly with non-cancer diagnoses. Breathlessness is a complex sensation with at least three dimensions--intensity, distress/unpleasantness and its impact on function. It is the conscious representation of a mismatch between central ventilatory drive (the demand to breathe) and the responding respiratory output (the ability to breathe). Measurement relies on subjective reports by patients using a choice of uni- and multi-variable tools; the minimal clinically important difference is the smallest change conceived as clinically meaningful by the patients. Exogenous and endogenous opioids work centrally to reduce the sensation of breathlessness, with morphine as a mu opioid receptor agonist the most widely studied. Regular, low doses of sustained-release morphine have been shown to safely reduce breathlessness in this setting without evidence of respiratory depression nor obtundation. Patients should be initiated at a dosage of 10 mg/24 h and titrated by 10 mg if there is no benefit once in steady state. The highest dosage in the only dose-ranging study published to date was only 30 mg/24 h. Predictors of response to opioids for chronic refractory breathlessness include younger people with more severe breathlessness at baseline. Future research should address whether upward titration delivers further clinical benefit and whether all underlying aetiologies respond as predictably to opioids.

Evidence-based intervention for chronic refractory breathlessness: practical therapies that make a difference

Chronic breathlessness which is refractory to treatments for the underlying condition is a common symptom of frequently encountered conditions that present in primary care, including lung and heart disease, and cancer. Primary-care based chronic illness initiatives such as clinics for asthma or chronic obstructive pulmonary disease (COPD) and community heart nurse specialists play a vital role in optimising the management of the underlying condition(s), but for many people, especially in the later stages of the disease, breathlessness persists (chronic refractory breathlessness). Chronic refractory breathlessness is distressing for patients, their families and other caregivers, and for clinicians. #### Clinical Question What can the primary care practitioner offer patients with chronic breathlessness at rest or on minimal exertion which is refractory to treatments directed at the underlying cause of the symptom? Clinically, chronic refractory breathlessness is a distinct entity, rather than simply a failure to treat the underlying condition(s). It requires a different approach than that required for acute breathlessness brought on, for example, by acute coronary syndrome, an acute exacerbation of COPD, or acute pneumonia. The evidence base for the management of chronic refractory breathlessness has progressed in the past decade. Several therapies now have high quality evidence to support their use (sustained release opioids, non-pharmacological interventions) and there is high-quality evidence that oxygen should not be used for people with normal oxygen saturation. Some therapies require further research (such as benzodiazepines and antidepressants) (Box 1). #### Box 1. Evidence for interventions in chronic refractory breathlessness For …

Breathlessness – current and emerging mechanisms, measurement and management: A discussion from an European Association of Palliative Care workshop

Background: A pre-conference workshop at the 2012 European Association of Palliative Care meeting discussed the current scientific and clinical aspects of breathlessness. Aim: To describe a current overview of clinically relevant science in breathlessness. Design: A collation of workshop presentations and discussions. Data sources: Narrative review. Results: The mismatch between the drive to breathe and the ability to breathe underlies the major theories of breathlessness unifying central processing of peripheral inputs including more recent recognition of the importance of peripheral muscles in mediating efferent inputs, supporting reduction of breathlessness with muscle conditioning. Key questions are whether there is a ‘final common pathway’ for breathlessness? Are the central nervous system targets for reducing breathlessness identical irrespective of underlying aetiology? Central nervous system functional imaging confirms an ability to differentiate severity (intensity) from affective components (unpleasantness). Breathlessness generates suffering across the community for patients and their caregivers often for long periods. The exertional nature of breathlessness means that reduction rather than elimination of the symptom is the therapeutic goal. No single intervention is likely to relieve chronic refractory breathlessness, but interventions made up of several components may provide incremental relief. Having optimally treated any underlying reversible components, the resultant chronic refractory breathlessness can be treated with pharmacological, psychological and physical therapies to reduce the sensation and its impacts. Conclusion: Ensuring optimal delivery of interventions for breathlessness, whose design is underpinned by improving the understanding in the aetiology and maintenance of breathlessness, is the subject of ongoing controlled clinical trials.

The Longitudinal Pattern of Response When Morphine Is Used To Treat Chronic Refractory Dyspnea

While evidence supports using sustained release morphine for chronic refractory breathlessness, little is known about the longitudinal pattern of breathlessness intensity as people achieve symptomatic benefit. The aim of this study is to describe this pattern. This secondary analysis used breathlessness intensity scores (100 mm visual analogue scale (VAS)) from a prospective, dose increment study of once daily (morning) sustained release morphine for chronic refractory breathlessness. Participants who achieved <10% improvement over their own baseline at one week (10 mg) were titrated to 20 mg and if no response, another week later to 30 mg for one week. Time was standardized at the first day of the week in which participants responded generating twice daily data one week either side of symptomatic benefit. Analysis used random effect mixed modeling. Of the 83 participants, 17/52 responders required >10 mg: 13 participants (20 mg) and 4 (30 mg), contributing 634 VAS observations. In the week leading to a response, average VAS scores worsened by 0.3 mm/day (p=0.16); the average improvement in the first 24 hours of response was 10.9 mm (7.0 to 14.7; p<0.0001), with continued improvement of 2.2 mm/day (p<0.001) for six more days. When treating chronic refractory breathlessness with once daily sustained release morphine, titrate to effect, since inadequate dose may generate no response; and following an initial response, further dose increases should not occur for at least one week. Whether further benefit would be derived beyond day six on the dose to which people respond, and what net effect a further dose increase would have are questions yet to be answered.

Clinically Important Differences in the Intensity of Chronic Refractory Breathlessness

ContextClinically important differences in chronic refractory breathlessness are ill defined but important in clinical practice and trial design. ObjectivesTo estimate the clinical relevance of differences in breathlessness intensity using distribution and patient anchor methods. MethodsThis was a retrospective data analysis from 213 datasets from four clinical trials for refractory breathlessness. Linear regression was used to explore the relationship between study effect size and change in breathlessness score (0–100mm visual analogue scale) and to estimate the change in score equivalent to small, moderate, and large effect sizes. Pooled individual blinded patient preference data from three randomized controlled trials were analyzed. The difference between the mean change in Day 4 minus baseline scores between preferred and non-preferred arms was calculated. ResultsThere was a strong relationship between change in score and effect size (P = 0.001; R2 = 0.98). Values for small, moderate, and large effects were −5.5, −11.3, and −18.2mm. The participant preference change in score was −9mm (95% CI, −15.8, −2.1) (P = 0.008). ConclusionThis larger dataset supports a clinically important difference of 10mm. Studies should be powered to detect this difference.

The Role of Benzodiazepines in Breathlessness: A Single Site, Open Label Pilot of Sustained Release Morphine Together with Clonazepam

Breathlessness at rest or on minimal exertion despite optimal treatment of underlying cause(s) is distressing and prevalent. Opioids can reduce the intensity of chronic refractory breathlessness and an anxiolytic may be of benefit. This pilot aimed to determine the safety and feasibility of conducting a phase III study on the intensity of breathlessness by adding regular benzodiazepine to low-dose opioid. This is a single site, open label phase II study of the addition of regular clonazepam 0.5 mg nocte orally to Kapanol(R) 10 mg (sustained release morphine sulphate) orally mane together with docusate/sennosides in people with modified Medical Research Council Scale ≥2. Breathlessness intensity on day four was the efficacy outcome. Participants could extend for another 10 days if they achieved >15% reduction over their own baseline breathlessness intensity. Eleven people had trial medication (eight males, median age 78 years (68 to 89); all had COPD; median Karnofsky 70 (50 to 80); six were on long-term home oxygen. Ten people completed day four. One person withdrew because of unsteadiness on day four. Five participants reached the 15% reduction, but only three went on to the extension study, all completing without toxicity. This study was safe, feasible and there appears to be a group who derive benefits comparable to titrated opioids. Given the widespread use of benzodiazepines for the symptomatic treatment of chronic refractory breathlessness and its poor evidence base, there is justification for a definitive phase III study.

Opioids for chronic refractory breathlessness: patient predictors of beneficial response

Chronic refractory breathlessness is common and distressing in advanced disease. Despite level I evidence to support the use of opioids for this symptom, not all patients benefit. This study aimed to discover which patient characteristics predict those most likely to gain improvement in breathlessness. This is an international, multicentre, retrospective analysis of 213 individual pooled datasets from four clinical trials of an opioid for chronic refractory breathlessness. "Response to opioid" was defined as 1) an absolute value of ≥ 10 mm improvement on the visual analogue scale (VAS) and 2) a relative value of ≥ 10% improvement from baseline VAS. We investigated baseline predictors using logistic regression. In the final model, higher baseline breathlessness intensity scores strongly predicted absolute and relative response (p<0.001). Younger age also predicted relative response (p = 0.025); functional status and dominant cause of breathlessness did not. Some evidence supported the descriptor "not enough air", but was not statistically significant (p = 0.052). A therapeutic trial of opioids is appropriate, irrespective of the cause of the breathlessness or functional status. Younger people or those with worse breathlessness are more likely to benefit. Opioids have a role in the management of chronic refractory breathlessness, but net benefit for individuals must be optimised.

The Evidence Base for Oxygen for Chronic Refractory Breathlessness: Issues, Gaps, and a Future Work Plan

Breathlessness or “shortness of breath,” medically termed dyspnea, is a common and distressing symptom featuring strongly in advanced lung, cardiac, and neuromuscular diseases; its prevalence and intensity increase as death approaches. However, despite the increasing understanding in the genesis of breathlessness, as well as an increasing portfolio of treatment options, breathlessness is still difficult to manage and engenders helplessness in caregivers and health care professionals and fear for patients. Although hypoxemia does not appear to be the dominant driver for breathlessness in advanced disease, the belief that oxygen is important for the relief of acute, chronic, and acute-on-chronic shortness of breath is firmly embedded in the minds of patients, caregivers, and health care professionals. This article presents current understanding of the use of oxygen for treating refractory breathlessness in advanced disease. The objective is to highlight what is still unknown, set a research agenda to resolve these questions, and highlight methodological issues for consideration in planned studies.