BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 1 of 7
Clinical Review
CLINICAL REVIEW The management of chronic breathlessness in patients with advanced and terminal illness 12
3
Magnus P Ekström postdoctoral research fellow , Amy P Abernethy professor , David C Currow 2 professor Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden; 2Discipline of Palliative and Supportive Services, Flinders University, Adelaide, Australia; 3Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA 1
Breathlessness—the sensation of discomfort with breathing—is a major cause of impaired activity and suffering worldwide and is common among elderly people in the community and in people with advanced disease.1 w1 Proper evaluation and treatment of breathlessness is vital to improve patients’ quality of life. Importantly, the sensation of breathlessness that persists despite disease specific treatment can be relieved for many people. This review focuses on the management of refractory breathlessness, defined as breathlessness at rest or on limited exertion that persists despite optimal treatment of the underlying conditions, in advanced chronic disease, or towards the end of life.2 w4
What is breathlessness?
Breathlessness is defined by the American Thoracic Society as the “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.”w1 According to the present neurophysiological model, breathlessness is the awareness of a mismatch between the ventilator drive (the need to breathe) and the achieved ventilation (the ability to breathe).w1
Importantly, breathlessness is a sensation and not a physiological variable. The presence and severity of breathlessness cannot be predicted sufficiently for an individual from variables such as oxygen saturation, respiratory rate, and forced expiratory volume in one second.w2 w3 Distressing breathlessness may be present despite a normal breathing rate and can be absent in patients with severe respiratory compromise. Patients should be asked about their symptoms.
How common is it in advanced and terminal illness? Chronic breathlessness, often defined as breathlessness for more than 4-8 weeks, is highly prevalent in the community and especially in people with advanced disease, and it often intensifies near death. In a study from South Australia, 9% of the population and 17% aged more than 65 years had chronic breathlessness.1 In a similar Norwegian study, 13% of the general population were limited by breathlessness and 5% reported severe breathlessness.w5 Among 1556 patients admitted to five tertiary hospitals in the United States, about 50% reported breathlessness.w6 In a review of advanced and terminal disease, the prevalence of breathlessness was high across all diagnoses: cancer (16-77%), chronic heart failure (18-88%), and renal disease (11-82%), and particularly high in chronic obstructive pulmonary disease (56-98%).3
In a prospective study, the prevalence of breathlessness among 5862 patients attending specialized palliative care increased from 50% to 65% during the last three months of life.4 Patients with cancer had less breathlessness overall than patients with non-malignant disease but the breathlessness increased more before death, whereas patients with other diagnoses on average had more severe and constant breathlessness, often for many years. Despite receiving specialized palliative care, 26% of the patients reported severe breathlessness during the last three months of life.4 Patients with advanced illnesses need to be monitored closely as the clinical trajectories are highly variable.w7 An estimated 60% of all people dying in high income countries are in need of palliative care at some point.w8
Correspondence to: M P Ekström, The Respiratory Unit, Department of Medicine, Blekinge Hospital, Karlskrona, Sweden [email protected] Extra material supplied by the author (see http://www.bmj.com/content/349/bmj.g7617?tab=related#datasupp) Additional references Dual simultaneous pathways toward symptom relief of breathlessness in palliative care. Adapted from Abernethy et alw25 For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 2 of 7
CLINICAL REVIEW
The bottom line • Breathlessness is the subjective sensation of discomfort with breathing • It is a common cause of major suffering in people with advanced and terminal disease • Breathlessness should be measured routinely in patients with advanced disease and can be reduced by appropriate treatment • The preferred treatments for refractory breathlessness are pulmonary rehabilitation and oral low dose opioids • Evidence for use of benzodiazepines and supplemental oxygen (in the absence of severe hypoxemia) is lacking or inconsistent and these interventions are not recommended for refractory breathlessness • Consider early referral to specialist care (including palliative care) if the cause remains unclear or if the response to treatment is insufficient
Sources and selection criteria We searched Medline, the Cochrane Database of Systematic Reviews, reference lists of major reviews, guidelines and consensus documents, and personal records using the terms “dyspnea” and “breathlessness”. We focused on systematic reviews, meta-analyses, randomized controlled trials, and high quality observational studies in patients with advanced or terminal disease.
What is the impact of breathlessness? Both patients and carers report breathlessness as a distressing symptom.w9 To reduce breathlessness, patients limit their physical activity.w1 Several observational studies link breathlessness to a more sedentary lifestyle,w10 deconditioning (decreased physical fitness),w11 increased anxiety and depression,w11 w12 impaired quality of life,w11 w13 loss of the will to live near death,w14 increased likelihood of admission to hospital,w15 and earlier death.5 w13 Breathlessness can worsen in a spiral of interacting symptoms—it may, for example, both cause anxiety and worsen as a consequence of the anxiety.w16
How is it measured? The ideal method for measuring breathlessness is by patients’ self report.w1 In a recent cross sectional study of patients with lung cancer, agreement between patients and doctors on ratings of breathlessness was only 45%.w13
Several instruments exist for measuring different aspects of breathlessness, such as intensity, unpleasantness, and functional impact.w1 Patients should use a simple tool, such as a numerical rating scale, to rate the severity of their breathlessness. They could be asked to rate the severity of their breathlessness “right now” or as an average over the past 12 or 24 hours, depending on the clinical setting. A numerical rating scale—a categorical 11 point scale between 0 (no breathlessness) to 10 (worst possible breathlessness)—is reliable and valid for measuring changes in breathlessness in individual patients.w1 w17 The same tool should be used to measure changes over time and response to treatment. According to a recent pooled analysis of trials on opioids for chronic breathlessness, a difference of 1 point on a numerical rating scale was identified as a clinically meaningful change in chronic breathlessness by patients.6 In people with critical illness who are unable to self report, the severity of breathlessness can be estimated using the validated respiratory distress observation scale based on eight observer rated clinical variables.7
How is it evaluated? Breathlessness may be the first presentation of a disease or may represent worsening of a pre-existing condition. The evaluation of breathlessness should identify all contributing causes that are amenable to treatment,w1 along with taking a medical history, carrying out a physical examination, and requesting basic tests.2 8 The extent of the evaluation needs to be guided by the patient’s
For personal use only: See rights and reprints http://www.bmj.com/permissions
wishes, expected benefits and harms from investigations and subsequent interventions, and the stage of disease.
In a study of 129 patients aged 60 years or older in primary care, chronic breathlessness was mainly associated with respiratory disease (53%), heart disease (21%), obesity (16%), and deconditioning (4%).8 Differential diagnoses (table⇓) include asthma, chronic obstructive pulmonary disease, interstitial lung disease, heart failure, ischemic heart disease, anemia, chronic pulmonary embolism, pleural effusion, obesity, and neuromuscular disease.2 8 w1 w18 In any advanced disease, breathlessness will increase with worsening cachexia.8
In one study a thorough history and medical examination was shown to correctly identify 55% of definitive causes of unexplained breathlessness.2 The table lists the clinical features suggestive of different underlying causes. A history of wheezing, productive cough (sputum), and palpitations suggests a cardiopulmonary disease.w18 Breathlessness described as “chest tightness” is suggestive of bronchospasm due to asthma.w1 w18 Breathlessness that is precipitated by lying down (orthopnea) is non-specific and seen in patients with heart failure, chronic obstructive pulmonary disease, obesity, and neuromuscular impairment.w18 A structured diagnostic algorithm including basic laboratory tests, electrocardiography, chest radiography, spirometry, and additional investigations as indicated, can establish a underlying cause of breathlessness in most patients.2 At least 20% of patients have several contributing causes.2 w1 w18 If the cause of chronic breathlessness remains unclear, or if patients have severe distress or complicating factors, early referral to a cardiologist, pulmonologist, or breathlessness clinic could be considered.9
What is the approach to management? The treatment of breathlessness involves interventions such as psychosocial support and walking aids, optimized treatment of underlying diseases and complications, relief of coexisting symptoms such as pain contributing to breathlessness, and treatment directed against deconditioning and the sensation of breathlessness itself (figure⇓). There is level I evidence for the use of pulmonary rehabilitation, especially in people with chronic obstructive pulmonary disease, and for systemic, low dose, sustained release opioids in patients with advanced disease.10-12 w1 Supplemental oxygen, in the absence of severe hypoxemia, and benzodiazepines are not recommended for breathlessness owing to inconsistent or no evidence of a net clinical benefit.13-15
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BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 3 of 7
CLINICAL REVIEW
Symptomatic under-treatment remains an important problem.16 In a population based study of patients with cancer, 9% had to visit the emergency department during the last six months of life and 5% during the last two weeks.w19 The main reasons included pain, malaise, nausea, constipation, and breathlessness—causes that may be avoidable with appropriate symptomatic treatment and follow-up.w19 The management should, importantly, address wishes, expectations, fears and concerns of the patient and family and carers. Patients may have concerns about the side effects of drugs, addiction, tolerance, and approaching the end of life. One approach is to develop a treatment model that tackles underlying causes whenever possible and that simultaneously treats the symptom itself (see web extra figure). If the cause of the breathlessness is unclear, if the symptoms are causing considerable distress, or there is insufficient treatment response on breathlessness, consider referral to specialty care (including palliative care).
What non-drug interventions are available for refractory breathlessness? Pulmonary rehabilitation
Strong evidence suggests that pulmonary rehabilitation decreases breathlessness, increases exercise capacity, and improves quality of life in patients with symptomatic cardiopulmonary limitation.11 A Cochrane analysis of 12 studies (323 patients) showed a clinically meaningful improvement in breathlessness on the chronic respiratory questionnaire (mean 1.1 points, 95% confidence interval 0.9 to 1.3) compared with usual care.17 Eligible patients include those who become breathless at least when hurrying on the level or walking up a slight hill.11 Most evidence pertains to chronic obstructive pulmonary disease, but there is some evidence of benefit also in interstitial lung disease and cancer.11 Multidisciplinary rehabilitation should be offered for at least six weeks and includes endurance and strength training, improved breathing techniques, and an opportunity for smoking cessation, optimized treatment of underlying conditions, and nutritional and psychosocial support.11 Pulmonary rehabilitation is beneficial and safe in patients with stable comorbidity, including cardiovascular disease and respiratory failure.11 18 Real world data are needed on the long term effects and how to improve uptake and feasibility of tailored rehabilitation programs in patients with advanced disease.
Multidisciplinary support services In a recent single blinded randomized trial of 105 consecutive patients with advanced disease (54% with chronic obstructive pulmonary disease, 20% with cancer, and 18% with interstitial lung disease), the patients’ “mastery” of breathlessness was improved by an multidisciplinary breathlessness support service, involving respiratory medicine, physiotherapy, occupational therapy, and palliative care management. On the mastery domain of the chronic respiratory questionnaire the mean difference was 0.58 (95% confidence interval 0.1 to 1.15) over six weeks compared with usual care, which could be clinically important for patients.19 Interestingly, the multidisciplinary intervention was also associated with improved survival.19
Non-invasive ventilation In a recent randomized trial of 200 patients with advanced solid cancers and acute respiratory failure, non-invasive ventilation was associated with a decrease in breathlessness compared with For personal use only: See rights and reprints http://www.bmj.com/permissions
oxygen therapy and the need for morphine; a mean decrease of 0.58 points (95% confidence interval 0.23 to 0.92) on the Borg scale (12 point ordinal scale between 0 “nothing at all” and 10 “maximal” breathlessness).20 Non-invasive ventilation improves breathlessness in acute hypercapnic respiratory failure due to chronic obstructive pulmonary disease.w24 In the setting of palliative care, non-invasive ventilation should only be used if it is tolerated by the patient and provides symptomatic relief; further studies of efficacy and feasibility are needed.21
Other non-drug interventions A Cochrane analysis of non-drug interventions for the relief of breathlessness reported moderate evidence for use of walking aids (for example, the rollator, a wheeled walking frame) as needed.w21 Evidence supported the use of chest wall vibration and neuroelectrical muscle stimulation,w21 although the utility of these two modalities may be limited in clinical practice. A handheld fan directed toward the mouth and nose may relieve breathlessness and might be tried especially in relatively immobilized patients.w21 w22 Although the efficacy of fan use is the subject of ongoing studies, it is inexpensive and has no reported side effects.22
What drug interventions are available for refractory breathlessness? Opioids
The preferred treatment for the relief of chronic refractory breathlessness is a systemic (oral or parenteral) low dose opioid (level I evidence).10 12 The effect of opioids seems to be mediated mainly by a central reduction of the ventilator demand and altered perception of breathlessness.23 w1 In a meta-analysis of nine small, randomized studies (116 patients) and an adequately powered randomized crossover trial (48 outpatients), systemic opioids reduced the mean chronic breathlessness by approximately 20% over baseline.10 12 Nebulized opioids are not recommended, given the current evidence.12
Which patients should be treated with opioids?
Trials included mainly patients with severe chronic obstructive pulmonary disease (and a few with restrictive pulmonary disease, cancer, or heart failure) and breathlessness at rest or minimal exertion limiting daily activities despite optimized treatments. In a pooled analysis, the benefit from opioids was stronger in younger patients and in those with severe breathlessness.24 Data in severe chronic heart failure are limited,25 26 but evidence that the benefit depends on the type of underlying disease is inconsistent.6
Which opioid dose is needed to relieve chronic breathlessness?
In an observational dose titration study of oral opioids 64% of the 83 patients reported a reduction in breathlessness.27 Of these, 70% responded to 10 mg regular, sustained release morphine daily and more than 90% responded to 20 mg morphine or less daily.27 The opioid effect seemed to increase during the week after each dose increment.w20 After three months, 53% of responders had sustained benefit from opioids without the need for doses to be increased.27 Importantly, regular, low dose, sustained release opioids seem to be safe in patients with advanced and terminal disease. Side effects are mainly nausea in the first two days of starting opioids, and constipation.10 12 27 No cases of respiratory depression or other serious adverse effects resulting in admission to hospital Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 4 of 7
CLINICAL REVIEW
or death have been reported in studies of low dose sustained release opioids.10 12 27 In a recent large observational study of patients with chronic respiratory failure associated with chronic obstructive pulmonary disease, low dose opioids were not associated with increased risk of admission to hospital or death.28 Data are needed on long term effects and on the net clinical benefit of opioids for breathlessness in less severe disease.
How is opioid treatment initiated and managed in practice?
The approach for chronic breathlessness is similar to that for opioid treatment of pain. Available evidence suggests that regular sustained release opioid is initiated in a dose equivalent to 10 mg oral morphine daily, and titrated upward, preferably once weekly, balancing beneficial and adverse effects.w20 All patients should receive prophylaxis and treatment against constipation.
Oxygen Oxygen is often given in the hope of relieving breathlessness, but the evidence for efficacy is inconsistent.13 14 29 There are no studies of oxygen for breathlessness in severe resting hypoxemia (arterial oxygen pressure
Page 1 of 7
Clinical Review
CLINICAL REVIEW The management of chronic breathlessness in patients with advanced and terminal illness 12
3
Magnus P Ekström postdoctoral research fellow , Amy P Abernethy professor , David C Currow 2 professor Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden; 2Discipline of Palliative and Supportive Services, Flinders University, Adelaide, Australia; 3Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA 1
Breathlessness—the sensation of discomfort with breathing—is a major cause of impaired activity and suffering worldwide and is common among elderly people in the community and in people with advanced disease.1 w1 Proper evaluation and treatment of breathlessness is vital to improve patients’ quality of life. Importantly, the sensation of breathlessness that persists despite disease specific treatment can be relieved for many people. This review focuses on the management of refractory breathlessness, defined as breathlessness at rest or on limited exertion that persists despite optimal treatment of the underlying conditions, in advanced chronic disease, or towards the end of life.2 w4
What is breathlessness?
Breathlessness is defined by the American Thoracic Society as the “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.”w1 According to the present neurophysiological model, breathlessness is the awareness of a mismatch between the ventilator drive (the need to breathe) and the achieved ventilation (the ability to breathe).w1
Importantly, breathlessness is a sensation and not a physiological variable. The presence and severity of breathlessness cannot be predicted sufficiently for an individual from variables such as oxygen saturation, respiratory rate, and forced expiratory volume in one second.w2 w3 Distressing breathlessness may be present despite a normal breathing rate and can be absent in patients with severe respiratory compromise. Patients should be asked about their symptoms.
How common is it in advanced and terminal illness? Chronic breathlessness, often defined as breathlessness for more than 4-8 weeks, is highly prevalent in the community and especially in people with advanced disease, and it often intensifies near death. In a study from South Australia, 9% of the population and 17% aged more than 65 years had chronic breathlessness.1 In a similar Norwegian study, 13% of the general population were limited by breathlessness and 5% reported severe breathlessness.w5 Among 1556 patients admitted to five tertiary hospitals in the United States, about 50% reported breathlessness.w6 In a review of advanced and terminal disease, the prevalence of breathlessness was high across all diagnoses: cancer (16-77%), chronic heart failure (18-88%), and renal disease (11-82%), and particularly high in chronic obstructive pulmonary disease (56-98%).3
In a prospective study, the prevalence of breathlessness among 5862 patients attending specialized palliative care increased from 50% to 65% during the last three months of life.4 Patients with cancer had less breathlessness overall than patients with non-malignant disease but the breathlessness increased more before death, whereas patients with other diagnoses on average had more severe and constant breathlessness, often for many years. Despite receiving specialized palliative care, 26% of the patients reported severe breathlessness during the last three months of life.4 Patients with advanced illnesses need to be monitored closely as the clinical trajectories are highly variable.w7 An estimated 60% of all people dying in high income countries are in need of palliative care at some point.w8
Correspondence to: M P Ekström, The Respiratory Unit, Department of Medicine, Blekinge Hospital, Karlskrona, Sweden [email protected] Extra material supplied by the author (see http://www.bmj.com/content/349/bmj.g7617?tab=related#datasupp) Additional references Dual simultaneous pathways toward symptom relief of breathlessness in palliative care. Adapted from Abernethy et alw25 For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 2 of 7
CLINICAL REVIEW
The bottom line • Breathlessness is the subjective sensation of discomfort with breathing • It is a common cause of major suffering in people with advanced and terminal disease • Breathlessness should be measured routinely in patients with advanced disease and can be reduced by appropriate treatment • The preferred treatments for refractory breathlessness are pulmonary rehabilitation and oral low dose opioids • Evidence for use of benzodiazepines and supplemental oxygen (in the absence of severe hypoxemia) is lacking or inconsistent and these interventions are not recommended for refractory breathlessness • Consider early referral to specialist care (including palliative care) if the cause remains unclear or if the response to treatment is insufficient
Sources and selection criteria We searched Medline, the Cochrane Database of Systematic Reviews, reference lists of major reviews, guidelines and consensus documents, and personal records using the terms “dyspnea” and “breathlessness”. We focused on systematic reviews, meta-analyses, randomized controlled trials, and high quality observational studies in patients with advanced or terminal disease.
What is the impact of breathlessness? Both patients and carers report breathlessness as a distressing symptom.w9 To reduce breathlessness, patients limit their physical activity.w1 Several observational studies link breathlessness to a more sedentary lifestyle,w10 deconditioning (decreased physical fitness),w11 increased anxiety and depression,w11 w12 impaired quality of life,w11 w13 loss of the will to live near death,w14 increased likelihood of admission to hospital,w15 and earlier death.5 w13 Breathlessness can worsen in a spiral of interacting symptoms—it may, for example, both cause anxiety and worsen as a consequence of the anxiety.w16
How is it measured? The ideal method for measuring breathlessness is by patients’ self report.w1 In a recent cross sectional study of patients with lung cancer, agreement between patients and doctors on ratings of breathlessness was only 45%.w13
Several instruments exist for measuring different aspects of breathlessness, such as intensity, unpleasantness, and functional impact.w1 Patients should use a simple tool, such as a numerical rating scale, to rate the severity of their breathlessness. They could be asked to rate the severity of their breathlessness “right now” or as an average over the past 12 or 24 hours, depending on the clinical setting. A numerical rating scale—a categorical 11 point scale between 0 (no breathlessness) to 10 (worst possible breathlessness)—is reliable and valid for measuring changes in breathlessness in individual patients.w1 w17 The same tool should be used to measure changes over time and response to treatment. According to a recent pooled analysis of trials on opioids for chronic breathlessness, a difference of 1 point on a numerical rating scale was identified as a clinically meaningful change in chronic breathlessness by patients.6 In people with critical illness who are unable to self report, the severity of breathlessness can be estimated using the validated respiratory distress observation scale based on eight observer rated clinical variables.7
How is it evaluated? Breathlessness may be the first presentation of a disease or may represent worsening of a pre-existing condition. The evaluation of breathlessness should identify all contributing causes that are amenable to treatment,w1 along with taking a medical history, carrying out a physical examination, and requesting basic tests.2 8 The extent of the evaluation needs to be guided by the patient’s
For personal use only: See rights and reprints http://www.bmj.com/permissions
wishes, expected benefits and harms from investigations and subsequent interventions, and the stage of disease.
In a study of 129 patients aged 60 years or older in primary care, chronic breathlessness was mainly associated with respiratory disease (53%), heart disease (21%), obesity (16%), and deconditioning (4%).8 Differential diagnoses (table⇓) include asthma, chronic obstructive pulmonary disease, interstitial lung disease, heart failure, ischemic heart disease, anemia, chronic pulmonary embolism, pleural effusion, obesity, and neuromuscular disease.2 8 w1 w18 In any advanced disease, breathlessness will increase with worsening cachexia.8
In one study a thorough history and medical examination was shown to correctly identify 55% of definitive causes of unexplained breathlessness.2 The table lists the clinical features suggestive of different underlying causes. A history of wheezing, productive cough (sputum), and palpitations suggests a cardiopulmonary disease.w18 Breathlessness described as “chest tightness” is suggestive of bronchospasm due to asthma.w1 w18 Breathlessness that is precipitated by lying down (orthopnea) is non-specific and seen in patients with heart failure, chronic obstructive pulmonary disease, obesity, and neuromuscular impairment.w18 A structured diagnostic algorithm including basic laboratory tests, electrocardiography, chest radiography, spirometry, and additional investigations as indicated, can establish a underlying cause of breathlessness in most patients.2 At least 20% of patients have several contributing causes.2 w1 w18 If the cause of chronic breathlessness remains unclear, or if patients have severe distress or complicating factors, early referral to a cardiologist, pulmonologist, or breathlessness clinic could be considered.9
What is the approach to management? The treatment of breathlessness involves interventions such as psychosocial support and walking aids, optimized treatment of underlying diseases and complications, relief of coexisting symptoms such as pain contributing to breathlessness, and treatment directed against deconditioning and the sensation of breathlessness itself (figure⇓). There is level I evidence for the use of pulmonary rehabilitation, especially in people with chronic obstructive pulmonary disease, and for systemic, low dose, sustained release opioids in patients with advanced disease.10-12 w1 Supplemental oxygen, in the absence of severe hypoxemia, and benzodiazepines are not recommended for breathlessness owing to inconsistent or no evidence of a net clinical benefit.13-15
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BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 3 of 7
CLINICAL REVIEW
Symptomatic under-treatment remains an important problem.16 In a population based study of patients with cancer, 9% had to visit the emergency department during the last six months of life and 5% during the last two weeks.w19 The main reasons included pain, malaise, nausea, constipation, and breathlessness—causes that may be avoidable with appropriate symptomatic treatment and follow-up.w19 The management should, importantly, address wishes, expectations, fears and concerns of the patient and family and carers. Patients may have concerns about the side effects of drugs, addiction, tolerance, and approaching the end of life. One approach is to develop a treatment model that tackles underlying causes whenever possible and that simultaneously treats the symptom itself (see web extra figure). If the cause of the breathlessness is unclear, if the symptoms are causing considerable distress, or there is insufficient treatment response on breathlessness, consider referral to specialty care (including palliative care).
What non-drug interventions are available for refractory breathlessness? Pulmonary rehabilitation
Strong evidence suggests that pulmonary rehabilitation decreases breathlessness, increases exercise capacity, and improves quality of life in patients with symptomatic cardiopulmonary limitation.11 A Cochrane analysis of 12 studies (323 patients) showed a clinically meaningful improvement in breathlessness on the chronic respiratory questionnaire (mean 1.1 points, 95% confidence interval 0.9 to 1.3) compared with usual care.17 Eligible patients include those who become breathless at least when hurrying on the level or walking up a slight hill.11 Most evidence pertains to chronic obstructive pulmonary disease, but there is some evidence of benefit also in interstitial lung disease and cancer.11 Multidisciplinary rehabilitation should be offered for at least six weeks and includes endurance and strength training, improved breathing techniques, and an opportunity for smoking cessation, optimized treatment of underlying conditions, and nutritional and psychosocial support.11 Pulmonary rehabilitation is beneficial and safe in patients with stable comorbidity, including cardiovascular disease and respiratory failure.11 18 Real world data are needed on the long term effects and how to improve uptake and feasibility of tailored rehabilitation programs in patients with advanced disease.
Multidisciplinary support services In a recent single blinded randomized trial of 105 consecutive patients with advanced disease (54% with chronic obstructive pulmonary disease, 20% with cancer, and 18% with interstitial lung disease), the patients’ “mastery” of breathlessness was improved by an multidisciplinary breathlessness support service, involving respiratory medicine, physiotherapy, occupational therapy, and palliative care management. On the mastery domain of the chronic respiratory questionnaire the mean difference was 0.58 (95% confidence interval 0.1 to 1.15) over six weeks compared with usual care, which could be clinically important for patients.19 Interestingly, the multidisciplinary intervention was also associated with improved survival.19
Non-invasive ventilation In a recent randomized trial of 200 patients with advanced solid cancers and acute respiratory failure, non-invasive ventilation was associated with a decrease in breathlessness compared with For personal use only: See rights and reprints http://www.bmj.com/permissions
oxygen therapy and the need for morphine; a mean decrease of 0.58 points (95% confidence interval 0.23 to 0.92) on the Borg scale (12 point ordinal scale between 0 “nothing at all” and 10 “maximal” breathlessness).20 Non-invasive ventilation improves breathlessness in acute hypercapnic respiratory failure due to chronic obstructive pulmonary disease.w24 In the setting of palliative care, non-invasive ventilation should only be used if it is tolerated by the patient and provides symptomatic relief; further studies of efficacy and feasibility are needed.21
Other non-drug interventions A Cochrane analysis of non-drug interventions for the relief of breathlessness reported moderate evidence for use of walking aids (for example, the rollator, a wheeled walking frame) as needed.w21 Evidence supported the use of chest wall vibration and neuroelectrical muscle stimulation,w21 although the utility of these two modalities may be limited in clinical practice. A handheld fan directed toward the mouth and nose may relieve breathlessness and might be tried especially in relatively immobilized patients.w21 w22 Although the efficacy of fan use is the subject of ongoing studies, it is inexpensive and has no reported side effects.22
What drug interventions are available for refractory breathlessness? Opioids
The preferred treatment for the relief of chronic refractory breathlessness is a systemic (oral or parenteral) low dose opioid (level I evidence).10 12 The effect of opioids seems to be mediated mainly by a central reduction of the ventilator demand and altered perception of breathlessness.23 w1 In a meta-analysis of nine small, randomized studies (116 patients) and an adequately powered randomized crossover trial (48 outpatients), systemic opioids reduced the mean chronic breathlessness by approximately 20% over baseline.10 12 Nebulized opioids are not recommended, given the current evidence.12
Which patients should be treated with opioids?
Trials included mainly patients with severe chronic obstructive pulmonary disease (and a few with restrictive pulmonary disease, cancer, or heart failure) and breathlessness at rest or minimal exertion limiting daily activities despite optimized treatments. In a pooled analysis, the benefit from opioids was stronger in younger patients and in those with severe breathlessness.24 Data in severe chronic heart failure are limited,25 26 but evidence that the benefit depends on the type of underlying disease is inconsistent.6
Which opioid dose is needed to relieve chronic breathlessness?
In an observational dose titration study of oral opioids 64% of the 83 patients reported a reduction in breathlessness.27 Of these, 70% responded to 10 mg regular, sustained release morphine daily and more than 90% responded to 20 mg morphine or less daily.27 The opioid effect seemed to increase during the week after each dose increment.w20 After three months, 53% of responders had sustained benefit from opioids without the need for doses to be increased.27 Importantly, regular, low dose, sustained release opioids seem to be safe in patients with advanced and terminal disease. Side effects are mainly nausea in the first two days of starting opioids, and constipation.10 12 27 No cases of respiratory depression or other serious adverse effects resulting in admission to hospital Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g7617 doi: 10.1136/bmj.g7617 (Published 2 January 2015)
Page 4 of 7
CLINICAL REVIEW
or death have been reported in studies of low dose sustained release opioids.10 12 27 In a recent large observational study of patients with chronic respiratory failure associated with chronic obstructive pulmonary disease, low dose opioids were not associated with increased risk of admission to hospital or death.28 Data are needed on long term effects and on the net clinical benefit of opioids for breathlessness in less severe disease.
How is opioid treatment initiated and managed in practice?
The approach for chronic breathlessness is similar to that for opioid treatment of pain. Available evidence suggests that regular sustained release opioid is initiated in a dose equivalent to 10 mg oral morphine daily, and titrated upward, preferably once weekly, balancing beneficial and adverse effects.w20 All patients should receive prophylaxis and treatment against constipation.
Oxygen Oxygen is often given in the hope of relieving breathlessness, but the evidence for efficacy is inconsistent.13 14 29 There are no studies of oxygen for breathlessness in severe resting hypoxemia (arterial oxygen pressure
