Chapter 10
Management of chronic breathlessness
Miriam J. Johnson1, Carlo Barbetta2, David C. Currow3, Matthew Maddocks4, Vanessa McDonald5, Ravi Mahadeva6 and Martina Mason7
1Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull, UK. 2Respiratory Medicine, S. Anna University Hospital, Ferrara, Italy. 3Palliative and Supportive Services, Flinders University, Adelaide, Australia. 4Palliative Care, Policy and Rehabilitation, King’s College London, London, UK. 5Respiratory and Sleep Medicine, Hunter Medical Research Institute, Newcastle, Australia. 6Dept of Medicine, University of Cambridge, Cambridge, UK. 7Respiratory Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK.
Correspondence: Miriam J. Johnson, Wolfson Palliative Care Research Centre, Hull York Medical School, Hertford Building, University of Hull, Hull, HU6 7RX, UK. E-mail: Miriam.johnson@hyms.ac.uk
Effective interventions for chronic breathlessness exist and are distinct from interventions directed at the pathophysiology of the medical condition causing the breathlessness. Some, like pulmonary rehabilitation, have been accepted by the clinical community and are integrated into respiratory care, at least in part and for people with COPD. Others, such as breathlessness clinics, are less well recognised but have strong evidence to support their use. A better understanding of the ways that can be used to integrate breathlessness management systematically alongside disease management should drive further implementation research. Low-dose, steady-state oral morphine has a developing evidence base in support of a net benefit. However, not all people tolerate opioids and further research into alternative drug options is needed to help this distressing symptom.
When a patient presents with breathlessness, it is fundamental that a careful search for the underlying cause of the symptom is conducted, a diagnosis of the medical condition is made, and treatment directed at that condition or conditions is initiated, optimised and monitored. Despite this, with many causes of breathlessness, patients will continue to experience breathlessness to a degree, or intermittently, especially if their disease progresses. If breathlessness itself is not seen by the patient as a legitimate concern to present to the clinician, and the clinician does not recognise the breathlessness as a potential therapeutic target in its own right even though the physiological measure may not alter, then the patient may be unable to access a range of evidence-based breathlessness interventions. Pulmonary rehabilitation is one such intervention. It has a strong evidence base and is accepted as part of management alongside disease-directed treatment, although this is not systematically provided or accessed. Further, other less well-known interventions, of which clinicians may be less aware, can improve this difficult symptom. This chapter summarises the current evidence base for breathlessness-directed interventions.
Non-pharmacological interventions
Complex interventions
Non-pharmacological treatments provide a foundation to manage breathlessness and address how the patient breathes (sensory-perceptive domain), thinks (affective domain) and functions (impact domain) (table 1) [1–3].
Table 1. Examples of non-pharmacological interventions according to breathlessness domain
Patient focus | Breathing | Thinking | Functioning |
Breathlessness domain | Sensory-perceptive experience | Affective distress | Symptom impact or burden |
Treatments (by primary target or mechanism of effect) | Breathing retraining | Relaxation | Physical exercise |
Complex services (multiple treatment) | Pulmonary rehabilitation | ||
Physical inactivity is a major consequence of breathlessness. This can precipitate a downward spiral of disease and reduced function [4]. A rehabilitation approach is recommended to counter this spiral. Pulmonary rehabilitation represents the gold standard [5, 6] and should be provided for patients who can tolerate the course. Programmes can address the distress and burden related to breathlessness, provide education in self-management and a supportive environment for patients to retain or regain control of their health behaviour [5]. Pulmonary rehabilitation provides a benchmark against which to compare the effects of other treatments. Breathlessness and mastery scores on the Chronic Respiratory Questionnaire improve by 0.79 (95% CI 0.56−1.03) and 0.71 (95% CI 0.47−0.95) points respectively, and in the majority of patients exercise performance improves beyond the minimally important clinical difference (MCID) for any given test [6]. The affective and impact domains of breathlessness can improve even in the absence of physiological change [7]; a patient’s perceived inability to physically train should not prevent programme referral. It can be challenging to encourage patients to start a programme, particularly in the presence of advanced disease when prognosis can be uncertain, practical issues such as attending the venue when frail, and fears about the ability to comply with the required level of exercise. The assurance that breathlessness per se is not dangerous, and will often settle with rest, is a prerequisite to encouraging exercise in people with refractory breathlessness. Even when exercising to a symptom-limited maximum, the intensity of breathlessness will recover rapidly (<5 min) [8]. Physical activity should be promoted and where relevant supported by the provision of appropriate mobility aids [9] and/or assistive equipment [10]. These can enhance functional exercise performance through increased ventilatory capacity and/or walking efficiency [11]. Where upper limb tasks, such as cooking or dressing, are limited by breathlessness [12], arm exercise training can also be used to good effect [13].
People who cannot tolerate a full programme of pulmonary rehabilitation because of advanced disease may benefit from chronic breathlessness intervention services that provide many of the same components, but in an individually tailored manner, and in fewer sessions. Three phase 3 RCTs have confirmed the benefit for breathlessness and such approaches should be considered [14–16]. A subprotocol [17] of the trial by FARQUHAR et al. [15] tested the intervention in people with non-malignant disease. Unlike the trial in cancer patients, although a beneficial trend was seen, this was not statistically significant. This mixed-methods study, however, reported clear narrative from the qualitative interviews of value to the participants, including value of the study interview itself. The authors discussed whether the therapeutic benefit of the interviews diluted the quantitatively measured primary outcome (distress due to breathlessness), especially in view of the different experience of people with cancer who often have had less time to find their own ways of managing breathlessness, but who typically have better access to supportive services [17]. A trial evaluating delivery of a breathing retraining intervention in patients with malignant lung disease compared a combination intervention (breathing training, anxiety management, relaxation, pacing, and prioritisation) delivered over three sessions compared to one training session. In both groups, there was a clinically significant improvement in breathlessness intensity; however, there was no difference between groups [18], suggesting a single training session was as effective. Furthermore, the distress due to breathlessness in the three-session group was worse (p=0.01). This is an important consideration for patients suffering a high symptom burden and impaired health status, such as those with lung cancer, where significant breathlessness is often a sign of poor prognosis.
Other non-pharmacological intervention components to relieve breathlessness have been studied, including: breathing retraining; handheld fans; chest wall vibration (CWV); neuromuscular electrical stimulation (NMES); and acupuncture and acupressure.
Breathing retraining involving pursed-lip breathing and diaphragmatic breathing can be delivered as a single or multidimensional intervention. Pursed-lip breathing may reduce respiratory rate and dynamic hyperinflation and may therefore be more effective in certain conditions than others, for example, COPD rather than interstitial fibrosis. Systematic reviews report moderate quality evidence to support the use of pursed-lip breathing in reducing breathlessness [2, 3].
Handheld fans have received an increasing amount of attention in the last few years, as a simple and cheap intervention for the relief of refractory breathlessness by directing cool air across the face [19–24]; they are discussed more fully in the next section.
CWV to relieve breathlessness in COPD patients is supported by strong evidence from five RCTs representing 97 participants with motor neuron disease or COPD [2]. While the mechanism is not completely understood, it is likely to involve activation of muscle spindles in the intercostal muscles [3].
NMES for the relief of breathlessness is supported by evidence from three studies representing 50 participants with COPD who used NMES over 4–6 weeks [2, 3, 25, 26]. NMES of the quadriceps also improves muscle strength and physical performance and can be used in conjunction with pulmonary rehabilitation or as an alternative for patients with severe COPD [2, 3].
Other non-pharmacological methods include acupuncture and acupressure, relaxation, distractive auditory stimuli and counselling; however, their evidence base remains inadequate [2, 3]. There is an urgent need for further well-designed trials in this field [27].
Summary
Non-pharmacological interventions for patients with refractory breathlessness are an important consideration for management. Multiple interventions are effective in relieving symptoms and improving health status and these interventions can be combined to deliver multidimensional strategies, tailored for individuals, even those with advanced disease.
The role of oxygen and airflow for the relief of chronic breathlessness
The role of oxygen therapy and facial airflow in relieving breathlessness in mildly hypoxaemic or normoxaemic patients is an interesting study area. There is emerging evidence to support the efficacy of airflow in chronic breathlessness; the mechanism of action may be the modulation of central perception [28] and reduction of central ventilator drive by airflow stimulation [29]. Airflow can be delivered from a cylinder of compressed medical air via a face mask, nasal cannulae, or handheld fan.
The use of oxygen in chronic breathlessness in patients with COPD was reviewed in a recent Cochrane systematic review and meta-analysis [30]. This review included 18 RCTs where a total of 427 participants with moderate-to-severe COPD and a mean PaO2 ≥7.3 kPa were randomised to supplemental oxygen or medical air delivered through a nasal cannula, mouthpiece or mask. Oxygen therapy led to significant reduction in breathlessness in mildly or non-hypoxaemic COPD patients, with a standardised mean difference (SMD) of −0.37 (95% CI −0.5– −0.24) compared to medical air. On further analysis, the significant reduction in breathlessness was only confirmed in 14 RCTs using continuous oxygen (SMD −0.46; 95% CI −0.59–0.33; clinically meaningful reduction of 12 mm (0–100 mm VAS)). Meta-analysis of secondary outcomes could not be performed due to heterogeneity in data presentation and outcome measures. Because of the heterogeneity of the included studies and small sample sizes, these data must be interpreted with caution. Two double-blind RCTs were published after this review. In contrast to the Cochrane review, they showed no significant reduction in breathlessness with palliative or ambulatory oxygen, compared to medical air [31, 32]. A systematic literature review examining the effect of oxygen in relieving dyspnoea in patients with advanced cancer or cardiac disease also failed to show significant benefit [33]. To date, the largest international, multicentre RCT examining the role of oxygen in mildly hypoxaemic or normoxaemic patients randomised 239 participants (63% COPD) to oxygen delivered via home oxygen concentrator for at least 15 h per day for 7 days during everyday general activity or to medical air [31]. A significant reduction in breathlessness intensity was observed in both study arms. Similarly, the other double-blind RCT tested ambulatory oxygen during general activity in 143 patients with COPD without resting hypoxaemia and showed significant benefit in both oxygen and medical air groups during the 12-week study period [32]. This latest evidence suggests that medical airflow may represent an active intervention rather than a placebo comparator.
The role of airflow delivered via a handheld fan was examined in three RCTs [20, 21, 24]. In an adequately powered crossover study, 50 inpatients with an advanced disease were randomised to handheld fan directed to their face or leg for 5 min at rest [20]. They reported a significant, 7-mm reduction in VAS (95% CI 2.5–11.7 mm; p=0.003) in the fan directed to face group. A feasibility study of 70 outpatients with COPD or cancer with a 2-month follow-up found no difference in breathlessness intensity (Modified Borg Dyspnoea Scale) with general activity. After 2 months, 48% of the handheld fan group still reported intervention use compared to 20% of the wristband group [24]. This did not reach statistical significance but the study was not designed to detect effectiveness. More recently, a feasibility cohort study of 31 patients using a handheld fan showed a mean±SD difference of −12.8±20.7 mm in VAS breathlessness following 5 min of airflow to the face while at rest [22]. These results support the benefit of handheld fans at rest, but their effectiveness and potential use in relieving dyspnoea in everyday general activity remains unconfirmed. However, change in breathlessness may not be the most appropriate primary outcome when assessing the effect of airflow on breathlessness in everyday activity, as patients’ level of breathlessness may increase or remain the same as their exercise tolerance increases. Appropriate outcome measures to reflect breathlessness improvement related to changes in exercise tolerance must, therefore, be identified.
A feasibility mixed-methods trial of the handheld fan [21] indicated that because the fan was cheap, had no side-effects, and was clearly used by patients as part of a complex intervention, which was consistent with other qualitative work [23], then further trials of the fan as a single component would not provide value of information.
Summary
The role of oxygen in relieving refractory breathlessness in patients with COPD with mild hypoxaemia and normoxaemia remains questionable; however, there is limited evidence that continuous exertional oxygen relieves breathlessness. Further research is needed to examine whether the benefit of oxygen therapy in normoxaemic patients outweighs any harm, and whether it is cost-effective. Understanding the mechanisms of breathlessness in specific COPD subgroups, e.g. major hyperinflation, airway obstruction, skeletal muscle deconditioning, obesity, and significant oxygen desaturation on exercise, would allow personalised therapies and would aid further research in this area.
The handheld fan should be considered as a component of complex intervention in the management of patients with refractory breathlessness. Future research should focus on implementing its use in clinical practice and further elucidating its mechanism of action [21].
Assisted ventilation and relief of breathlessness
NPPV refers to the application of positive pressure to the upper airway using a mask or similar device to augment ventilation. While the evidence base for NPPV is strong in certain clinical conditions, in others, it remains uncertain.
Ventilatory failure develops when there is an imbalance between the capacity of the respiratory muscle pump, the load placed on it and an inadequate ventilatory drive. Although the mechanism of ventilatory failure is not fully understood, in physiological studies NPPV improves lung mechanics, respiratory muscle strength and respiratory drive, and reduces ventilation–perfusion mismatch in patients with neuromuscular/restrictive extrathoracic respiratory disorders and hypercapnic COPD [34, 35]. The main areas of clinical use are in management of chronic ventilatory failure in extrapulmonary restrictive disease, neuromuscular disorders and COPD. NPPV is also used to manage acute ventilatory failure, particularly in exacerbations of COPD and acute cardiogenic pulmonary oedema, to reduce the requirement for intubation and support patients for whom intubation is considered inappropriate.
There is a strong evidence for NPPV use in acute ventilatory failure in COPD exacerbation; multiple RCTs have demonstrated reduced intubation, hospital length of stay and mortality rates [36]. No RCT has assessed the benefit of NPPV in patients with restrictive extrathoracic disease but case series indicate survival benefit in patients treated with NPPV [37–39]. A systematic literature review of people with neuromuscular and extrathoracic restrictive lung disease confirmed improved survival, quality of life (QoL) and gas exchange with ventilation [40, 41].
Although the effect of NPPV in patients with chronic, stable COPD has been examined in numerous RCTs, systematic reviews have showed no significant improvement in respiratory function [42, 43]. A recent meta-analysis provided no evidence of efficacy for NPPV in patients with stable hypercapnic COPD [44] but definite conclusions could not be drawn because of small study sample sizes.
The sensation of breathlessness strongly correlates with inspiratory load [45]. NPPV reduces inspiratory effort [33], which is possibly the mechanism by which it relieves breathlessness. RCTs examining the effect of NPPV have mainly focused on respiratory function with breathlessness assessed as a secondary outcome. The heterogeneity in assessment tools used has rendered comparison and generation of pooled outcomes impossible.
Four RCTs assessed NPPV in relieving breathlessness in acute exacerbations of COPD. Three studies reported clinically and statistically significant improvement in subjective breathlessness. PLANT et al. [46] reported more rapid relief in breathlessness in the NIV group but used unvalidated breathlessness scales with unknown MCID, making interpretation difficult. BOTT et al. [47] showed a significant difference (22 mm VAS) between groups. VAS breathlessness was assessed daily until day 3 and on the day of discharge. The median of the 3-day mean scores between the groups was significantly lower in the NIV group. Breathlessness data were presented graphically without any statistical analysis, thereby limiting interpretation. In addition, four patients could not tolerate NIV and were excluded from the analysis, making the conclusions questionable. KEENAN et al. [48] reported greater than MCID improvement in Borg score with NPPV, compared to the usual care group. Breathlessness was assessed at randomisation, 1 h after randomisation and then daily for the rest of the hospital stay. No significant difference in baseline Borg score between the NIV (5.8) and control (6.2) groups was noted. The Borg index between the groups was significantly lower at 1 h and day 2; however, breathlessness data were again only presented graphically. Nonetheless, visual comparison of the plotted data suggested clinically significant improvement in breathlessness in the NPPV group. This study was underpowered for the primary outcome and poor adherence in the NIV group led to possible underestimation of the NIV effect on breathlessness. KOLODZIEJ et al. [42] assessed the benefits of domiciliary NPPV on relieving breathlessness in patients with stable COPD. In this systematic review, four out of six RCTs demonstrated an improvement in breathlessness score in patients treated with nocturnal NPPV. RENSTON et al. [49] showed a 66.3% reduction in breathlessness (Borg) in 17 patients treated with NPPV versus a nonsignificant 27% reduction in the sham-treated NPPV group following 5 days of treatment. There was no significant difference between the NPPV and sham-treated NPPV group with regard to the modified Medical Research Council (MRC) dyspnoea scale or oxygen cost scales after 5 days of treatment. CASANOVA et al. [50] showed a significant reduction in breathlessness (Borg) in the NIV plus standard care group (96% long-term oxygen therapy (LTOT)), compared to the standard care group (93% LTOT) at 3 and 6 months (p=0.03). Using the MRC dyspnoea scale, CLINI et al. [51] reported significant reduction in breathlessness in 43 patients randomised to NPPV and LTOT, compared to LTOT at both 12 months (treatment effect 0.4; 95% CI 0.02–0.78) and 24 months (treatment effect 0.6; 95% CI 0.15–1.05). In the RCT by GARROD et al. [52], the breathlessness portion of the Chronic Respiratory Disease Questionnaire improved more in the NPPV and exercise group than in the exercise alone group after 12 weeks of follow-up, but this difference did not reach statistical significance (mean difference 3.29, 95% CI −1.26–7.84; p=0.15). However, exercise tolerance improved significantly better in the intervention group at 12 weeks, with a mean end study difference in shuttle walk distance of 65.8 m (95% CI 17.1–114 m). None of the trials in this review used breathlessness as a primary outcome measure; because of different outcome measures, data could not be pooled. Current consensus recommends initiation of long-term NPPV in people with obstructive lung disease and symptoms associated with ventilatory failure, including breathlessness, and those who develop significant gas exchange abnormality and fail to respond to optimal medical therapy [53].
The current consensus of professional societies on palliative NPPV for acute respiratory failure recognises its use in people for whom endotracheal intubation is inappropriate, provided the cause is reversible and NPPV improves patient comfort [54].
Summary
NPPV is not routinely recommended for use in non-hypercapnic individuals. However, the data to date support more research into the mechanisms of breathlessness and NPPV to identify the subgroups of people with intractable breathlessness most likely to receive palliation from NPPV. The current work on breathlessness phenotypes could facilitate a focused study with detailed breathlessness measures as a primary outcome.
Pharmacological interventions
Non-opioid drugs
Many drugs have been used empirically for breathlessness in clinical practice with the rationale that they may modulate the central perception and peripheral genesis of the symptom. Some are being investigated systematically with an emerging evidence base (e.g. opioids), but others have not, thus illustrating the need for systematic research in the field of chronic breathlessness [27]. A summary of studies is shown in table 2, which illustrates the paucity of phase 3 RCTs evaluating non-opioid drugs for breathlessness.
Table 2. Non-opioid drugs for breathlessness: benzodiazepines
First author [ref.] | Type of study | Drug tested | Patients enrolled | Breathlessness measure | Statistically significant benefit | Notes |
SIMON [55] | Cochrane systematic review | Diazepam | COPD | VAS | No | Small heterogeneous studies |
STEGE [56] | RCT | Temazepam | 14 severe normocapnic COPD | VAS | No | Safety¶ in normocapnic COPD |
CLEMENS [57] | Prospective, non-randomised | Lorazepam 1 mg and morphine as needed | 26 patients admitted to a palliative care unit | Numerical scale (0–10) | No | Safety¶ of co-administration |
ALLCROFT [58] | Open-label trial | Clonazepam 0.5 mg nocte and sustained-release morphine 10 mg | 11 COPD with modified MRC breathlessness scale >2 | VAS | 5 patients reported benefit | Safety¶ of co-administration |
GOMUTBUTRA [59] | Retrospective analysis of clinical records | Lorazepam | 115 between cancer, heart failure, COPD | 4-point dyspnoea scale | Yes, when opioids were co-administered with BDZ | Safety¶ of co-administration |
MRC: Medical Research Council; BDZ: benzodiazepine. #: grades breathlessness from 1 (little breathlessness) to 6 (extreme breathlessness); ¶: effect of benzodiazepines on breathing, ventilation and gas exchange. | ||||||
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