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It is likely that the burden of breathlessness in low and middle-income countries (LMICs) is much higher than has been estimated using calculations of disease burden and expected prevalence of the symptom. However, most breathlessness research has been conducted in high-income countries and may not be relevant to LMICs. To address this issue, we convened an international breathlessness and global health workshop. Our multidisciplinary team of experts (global palliative care, respiratory medicine, epidemiology, palliative medicine, psychiatry, sport science, global public health and health economics) met at the University of Hull for a two-day workshop in May 2024. We had 8 presentations on key issues relevant to global breathlessness research. Our discussions focussed on unexplored questions and links between breathlessness and other health and social issues, in order to develop an agenda for global breathlessness research. Our discussions highlighted (1) the global burden of breathlessness generated by a range of lifestyle, environmental, disease and poverty-related factors, (2) the need for a global healthcare workforce that can address modifiable causes and the symptoms of breathlessness together using an integrated approach, (3) the value of information over clinical effectiveness when considering implementation of breathlessness self-management interventions, (4) Addressing non-clinical outcomes which are meaningful to individuals and families and (5) Developing a language for global breathlessness research which does not assume that the cause of breathlessness is diagnosed or treated. We present our discussions and recommendations for new approaches and paradigms for global breathlessness research to generate discussion—not to provide empirical evidence.

Background: Persistent breathlessness is debilitating and increases in prevalence with advanced age and at end of life. This study aimed to evaluate any relationship between self-reported global impressions of change (GIC) in perceived health and breathlessness in older men. Design: Cross-sectional study of 73-year-old Swedish men in the VAScular and Chronic Obstructive Lung disease study. A postal survey included items on perceived changes in health and breathlessness (GIC scales) and breathlessness (assessed using the modified Medical Research Council [mMRC] breathlessness scale, Dyspnea-12 and Multidimensional Dyspnea Scale) since age 65. Results: Of 801 respondents, breathlessness (mMRC ?2) was reported by 17.9%, worsening breathlessness by 29.1%, and worsening perceived health by 51.3%. Worsening breathlessness was strongly correlated with worsening perceived health (Pearson's correlation coefficient of 0.68 [p?0.001] and Kendall's ? of 0.56 [p?

Abstract Introduction The battery-operated hand-held fan (‘fan’) is an inexpensive and portable non-pharmacological intervention for chronic breathlessness. Evidence from randomised controlled trials suggests the fan reduces breathlessness intensity and improves physical activity in patients with a range of advanced chronic conditions. Qualitative data from these trials suggests the fan may also reduce anxiety and improve daily functioning for many patients. This study aimed to explore barriers and facilitators to the fan’s implementation in specialist respiratory care as a non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD). Methods A qualitative approach was taken, using focus groups. Participants were clinicians from any discipline working in specialist respiratory care at two hospitals. Questions asked about current fan-related practice and perceptions regarding benefits, harms and mechanisms, and factors influencing its implementation. Analysis used a mixed inductive/deductive approach. Results Forty-nine participants from nursing (n = 30), medical (n = 13) and allied health (n = 6) disciplines participated across 9 focus groups. The most influential facilitator was a belief that the fan’s benefits outweighed disadvantages. Clinicians’ beliefs about the fan’s mechanisms determined which patient sub-groups they targeted, for example anxious or palliative/end-stage patients. Barriers to implementation included a lack of clarity about whose role it was to implement the fan, what advice to provide patients, and limited access to fans in hospitals. Few clinicians implemented the fan for acute-on-chronic breathlessness or in combination with other interventions. Conclusion Implementation of the fan in specialist respiratory care may require service- and clinician-level interventions to ensure it is routinely recommended as a first-line intervention for chronic breathlessness in patients for whom this symptom is of concern, regardless of COPD stage.

Abstract Background Not being able to work has negative health, social and financial consequences. Persisting breathlessness is prevalent in working-aged people. Is it associated with lower workforce participation? This study, using the South Australian Health Omnibus, aimed to explore associations between paid workforce participation and persisting breathlessness intensity, and economic impacts on income in people of working age. Methods This cross-sectional study conducted face-to-face interviews with a random sample of adults in South Australia (n = 8916). Questions included key demographic data, workforce participation and the presence and intensity of persisting breathlessness. Data from working-aged respondents (20–65 years of age) were standardised to the census for regression analyses. Work was coded to paid full- or part-time work or ‘other’. Persisting breathlessness (more than three of the last six months) used the modified Medical Research Council breathlessness scale (aggregated to 0, 1, 2–4). Opportunity cost valuations compared annual income foregone by persisting breathlessness severity. Results Of people interviewed, 6,608 were working-aged (49.9% male; 67.5% had post-secondary qualifications; 70.9% were in paid full- or part-time work; and 1.7% had mMRC score 2–4). Workforce participation dropped in working aged people with increasing breathlessness: mMRC 0, 70.6%; mMRC 1, 51.7%; mMRC 2–4, 20.3%. In the regression model, people with the most severe breathlessness were much less likely to work (OR 0.14; 95% CI 0.09, 0.22). Annual income foregone by people with persisting breathlessness was AU$10.7 billion (AU$9.1b for full-time and AU$1.6b for part-time work; range AU$5.9b, AU$49.7b). Conclusion Worsening persisting breathlessness is associated with lower workforce participation with direct financial consequences, greatest for older males.

Abstract Background Depression is prevalent in people with very poor prognoses (days to weeks). Clinical practices and perceptions of palliative physicians towards depression care have not been characterised in this setting. The objective of this study was to characterise current palliative clinicians’ reported practices and perceptions in depression screening, assessment and management in the very poor prognosis setting. Methods In this cross-sectional cohort study, 72 palliative physicians and 32 psychiatrists were recruited from Australian and New Zealand Society of Palliative Medicine and Royal Australian and New Zealand College of Psychiatrists between February and July 2020 using a 23-item anonymous online survey. Results Only palliative physicians results were reported due to poor psychiatry representation. Palliative physicians perceived depression care in this setting to be complex and challenging. 40.0% reported screening for depression. All experienced uncertainty when assessing depression aetiology. Approaches to somatic symptom assessment varied. Physicians were generally less likely to intervene for depression than in the better prognosis setting. Most reported barriers to care included the perceived lack of rapidly effective therapeutic options (77.3%), concerns of patient burden and intolerance (71.2%), and the complexity in diagnostic differentiation (53.0%). 66.7% desired better collaboration between palliative care and psychiatry. Conclusions Palliative physicians perceived depression care in patients with very poor prognoses to be complex and challenging. The lack of screening, variations in assessment approaches, and the reduced likelihood of intervening in comparison to the better prognosis setting necessitate better collaboration between palliative care and psychiatry in service delivery, training and research.

Background About 70% of patients with advanced cancer experience pain. Few studies have investigated the use of healthcare in this population and the relationship between pain intensity and costs. Methods Adults with advanced cancer and scored worst pain ≥ 2/10 on a numeric rating scale (NRS) were recruited from 6 Australian oncology/palliative care outpatient services to the Stop Cancer PAIN trial (08/15-06/19). Out-of-hospital, publicly funded services, prescriptions and costs were estimated for the three months before pain screening. Descriptive statistics summarize the clinico-demographic variables, health services and costs, treatments and pain scores. Relationships with costs were explored using Spearman correlations, Mann-Whitney U and Kruskal-Wallis tests, and a gamma log-link generalized linear model. Results Overall, 212 participants had median worst pain scores of five (inter-quartile range 4). The most frequently prescribed medications were opioids (60.1%) and peptic ulcer/gastro-oesophageal reflux disease (GORD) drugs (51.6%). The total average healthcare cost in the three months before the census date was A$6,742 (95% CI $5,637, $7,847), approximately $27,000 annually. Men had higher mean healthcare costs than women, adjusting for age, cancer type and pain levels (men $7,872, women $4,493, pConclusions In this population with pain and cancer, there was no clear relationship between healthcare costs and pain severity. These treatment patterns requiring further exploration including the prevalence of peptic ulcer/GORD drugs, and lipid lowering agents and the higher healthcare costs for men. Trial registration ACTRN12615000064505. World Health Organisation unique trial number U1111–1164–4649. Registered 23 January 2015.

Breathlessness is a common symptom suffered by people living with advanced malignant and non-malignant diseases, one which significantly limits their quality of life. If it emerges at minimal exertion, despite the maximal, guidelines-directed, disease-specific therapies, it should be considered persistent and obliges clinicians to prescribe symptomatic, non-pharmacological, and pharmacological treatment to alleviate it. Opioids are recommended for the symptomatic treatment of persistent breathlessness, with morphine most extensively studied for this indication. It is extensively metabolized in the liver into water-soluble 3- and 6-glucuronides, excreted by the kidneys. In the case of advanced renal failure, the glucuronides accumulate, mainly responsible for toxicity 3-glucuronides. Some people, predominantly those with advanced renal failure, develop neurotoxic effects after chronic morphine, even when prescribed at a very low dose. A single-center case series of consecutive patients experiencing neurotoxic effects after long-term, low-dose morphine or at risk of such effects were transferred to methadone to avoid the accumulation of neurotoxic metabolites. Over the course of 4.5 years, 26 patients have been treated with methadone in the median dose of 3.0 mg/24 h p.o., for persisting breathlessness. Sixteen of them had been treated previously with an opioid (usually morphine) at the median dose of 7.0 mg/24 h (morphine oral daily dose equivalent). They were transferred to methadone, with the median dose of 3.0 mg/24 h orally (methadone oral daily dose equivalent), and the median morphine-to-methadone dose ratio was 2.5:1. All patients experienced a meaningful improvement in breathlessness intensity after methadone, by a median of 5 points (range 1–8) on the 0–10 numerical rating scale (NRS) in the whole group, and by 2 points (range 0–8) in those pretreated with other opioids, mainly morphine. Low-dose methadone can be considered an efficient alternative to morphine for reducing breathlessness in people experiencing neurotoxic effects or at risk of developing them following treatment with morphine.

Introduction One-fifth of emergency department presentations by ambulance are due to acute-on-chronic breathlessness. We explored the feasibility of an evaluation-phase, cluster randomised controlled trial (cRCT) of the effectiveness and cost-effectiveness of a paramedic-administered, non-pharmacological breathlessness intervention for people with acute-on-chronic breathlessness at ambulance call-out (BREATHE) regarding breathlessness intensity and conveyance to hospital. Methods This mixed-methods, feasibility cRCT (ISRCTN80330546) randomised paramedics to usual care or intervention plus usual care. Retrospective patient consent to use call-out data (primary end-point) and prospective patient/carer consent for follow-up was sought. Potential primary outcomes included breathlessness intensity (numerical rating scale) and conveyance. Follow-up included: interviews with patients/carers and questionnaires at 14 days, 1 and 6 months; paramedic focus groups and surveys. Results Recruitment was during COVID-19, with high demands on paramedics and fewer call-outs by eligible patients. We enrolled 29 paramedics; nine withdrew. Randomisation/trial procedures were acceptable. Paramedics recruited 13 patients, not meeting recruitment target (n=36); eight patients and three carers were followed-up. Data quality was good but insufficient for future sample size estimation. The intervention did not extend call-out time, was delivered with fidelity and was acceptable to patients, carers and paramedics. There were no repeat call-outs within 48 h. All trained paramedics strongly recommended BREATHE as a highly relevant, simple intervention. Conclusion Patient recruitment to target was not feasible during the pandemic. Training and intervention were acceptable and delivered with fidelity. Results include valuable information on recruitment, consent, attrition and data collection that will inform the design and delivery of a definitive trial.

Objectives Although opioid prescribing and harms have increased in Australia, there is a lack of population-level evidence about the drivers of long-term opioid use, dependence and other harms. This study aims to profile the POPPY II cohort, with respect to sociodemographic and clinical health characteristics and patterns of opioid initiation. Approach The POPPY II cohort includes adult residents (≥18 years) in NSW who were initiated on prescribed opioids subsidised through Australia’s Pharmaceutical Benefits Scheme for any period between 1st July 2003 and 31st December 2018. The cohort has been linked to nine other datasets containing information on socio-demographic and clinical characteristics, health service use, and adverse outcomes. Results There were 3,569,433 people in the cohort. One in four people were aged ≥65 years at the time of opioid initiation (26.8%) and half were female (52.7%). About 71% resided in a major city. Approximately 6% had evidence of being treated for cancer in the year prior to opioid initiation (5.8%). In the 3 months prior to cohort entry, 27% used an analgesic medicine and 21% used a psychotropic medicine. Less than a third initiated on a strong opioid (22.2%) and the most commonly initiated opioid was paracetamol/codeine (61.3%). Conclusion The POPPY II study is the largest post-marketing surveillance study of prescribed opioids in Australia, and one of the largest studies worldwide. Understanding the characteristics of the cohort will inform future work aimed at generating robust evidence of the long-terms patterns and outcomes of prescribed opioid use in the Australian community.

Abstract Background A primary brain cancer diagnosis is a distressing, life changing event. It adversely affects the quality of life for the person living with brain cancer and their families (‘carers’). Timely access to evidence-based information is critical to enabling people living with brain cancer, and their carers, to self-manage the devastating impacts of this disease. Method A systematic environmental scan of web-based resources. A depersonalised search for online English-language resources published from 2009 to December 2019 and designed for adults (> 25 years of age), living with primary brain cancer, was undertaken using the Google search engine. The online information was classified according to: 1) the step on the cancer care continuum; 2) self-management domains (PRISMS taxonomy); 3) basic information disclosure (Silberg criteria); 4) independent quality verification (HonCode); 5) reliability of disease and treatment information (DISCERN Sections 1 and 2); and readability (Flesch-Kincaid reading grade). Results A total of 119 online resources were identified, most originating in England (n = 49); Australia (n = 27); or the USA (n = 27). The majority of resources related to active treatment (n = 76), without addressing recurrence (n = 3), survivorship (n = 1) or palliative care needs (n = 13). Few online resources directly provided self-management advice for adults living with brain cancer or their carers. Just over a fifth (n = 26, 22%) were underpinned by verifiable evidence. Only one quarter of organisations producing resources were HonCode certified (n = 9, 24%). The median resource reliability as measured by Section 1, DISCERN tool, was 56%. A median of 8.8 years of education was required to understand these online resources. Conclusions More targeted online information is needed to provide people affected by brain cancer with practical self-management advice. Resources need to better address patient and carer needs related to: rehabilitation, managing behavioural changes, survivorship and living with uncertainty; recurrence; and transition to palliative care. Developing online resources that don’t require a high level of literacy and/or cognition are also required.

Abstract This multi-site, double blind, parallel arm, fixed dose, randomised placebo controlled phase III study compared megestrol acetate 480 mg/day with dexamethasone 4 mg/day for their net effects on appetite in people with cancer anorexia. Patients with advanced cancer and anorexia for ≥ 2 weeks with a score ≤ 4 (0–10 numeric rating scale (NRS) 0 = no appetite, 10 = best possible appetite) were recruited. Participants received megestrol 480 mg or dexamethasone 4 mg or placebo daily for up to 4 weeks. Primary outcomes were at day 7. Responders were defined as having a ≥ 25% improvement in NRS over baseline. There were 190 people randomised (megestrol acetate n = 61; dexamethasone n = 67, placebo n = 62). At week 1 (primary endpoint), 79·3% in the megestrol group, 65·5% in the dexamethasone group and 58·5% in the placebo group (p = 0.067) were responders. No differences in performance status or quality of life were reported. Treatment emergent adverse events were frequent (90·4% of participants), and included altered mood and insomnia. Hyperglycemia and deep vein thromboses were more frequent when on dexamethasone than the other two arms. There was no difference in groups between the three arms, with no benefit seen over placebo with anorexia improving in all arms. Trail registration: The trial was registered on 19/08/2008 with the Australian New Zealand Clinical Trials Registry (ACTRN12608000405314).

Abstract Background Delirium is highly problematic in palliative care (PC). Preliminary data indicate a potential role for melatonin to prevent delirium, but no randomized controlled trials (RCTs) are reported in PC. Methods Patients aged ≥18 years, with advanced cancer, admitted to an inpatient Palliative Care Unit (PCU), having a Palliative Performance Scale rating ≥ 30%, and for whom consent was obtained, were included in the study. Patients with delirium on admission were excluded. The main study objectives were to assess the feasibility issues of conducting a double-blind RCT of exogenous melatonin to prevent delirium in PC: recruitment, retention, procedural acceptability, appropriateness of outcome measures, and preliminary efficacy and safety data. Study participants were randomized in a double-blind, parallel designed study to receive daily melatonin 3 mg or placebo orally at 21:00 over 28 days or less if incident delirium, death, discharge or withdrawal occurred earlier. Delirium was diagnosed using the Confusion Assessment Method. Efficacy endpoints in the melatonin and placebo groups were compared using time-to-event analysis: days from study entry to onset of incident delirium. Results Over 16 months, 60/616 (9.7%; 95% CI: 7.5–12.4%) screened subjects were enrolled. The respective melatonin (n = 30) vs placebo (n = 30) outcomes were: incident delirium in 11/30 (36.7%; 95%CI: 19.9–56.1%) vs 10/30 (33%; 95% CI: 17.3–52.8%); early discharge (6 vs 5); withdrawal (6 vs 3); death (0 vs 1); and 7 (23%) vs 11 (37%) reached the 28-day end point. The 25th percentile time-to-event were 9 and 18 days (log rank, χ2 = 0.62, p = 0.43) in melatonin and placebo groups, respectively. No serious trial medication-related adverse effects occurred and the core study procedures were acceptable. Compared to those who remained delirium-free during their study participation, those who developed delirium (n = 21) had poorer functional (p = 0.036) and cognitive performance (p = 0.013), and in particular, poorer attentional capacity (p = 0.003) at study entry. Conclusions A larger double-blind RCT is feasible, but both subject accrual and withdrawal rates signal a need for multisite collaboration. The apparent trend for shorter time to incident delirium in the melatonin group bodes for careful monitoring in a larger trial. Trial registration Registered on July 21st 2014 with ClinicalTrials.gov : NCT02200172 .

Abstract Background This analysis aims to evaluate health-related quality of life (HrQoL) (primary outcome for this analysis), nausea and vomiting, and pain in patients with inoperable malignant bowel obstruction (IMBO) due to cancer or its treatments randomised to standardised therapies plus octreotide or placebo over a maximum of 72 h in a double-blind clinical trial. Methods Adults with IMBO and vomiting recruited through 12 services spanning inpatient, consultative and community settings in Australia were randomised to subcutaneous octreotide infusion or saline. HrQoL was measured at baseline and treatment cessation (EORTC QLQ-C15-PAL). Mean within-group paired differences between baseline and post-treatment scores were analysed using Wilcoxon Signed Rank test and between group differences estimated using linear mixed models, adjusted for baseline score, sex, age, time, and study arm. Results One hundred six of the 112 randomised participants were included in the analysis (n = 52 octreotide, n = 54 placebo); 6 participants were excluded due to major protocol violations. Mean baseline HrQoL scores were low (octreotide 22.1, 95% CI 14.3, 29.9; placebo 31.5, 95% CI 22.3, 40.7). There was no statistically significant within-group improvement in the mean HrQoL scores in the octreotide (p = 0.21) or placebo groups (p = 0.78), although both groups reported reductions in mean nausea and vomiting (octreotide p

Background: Chronic breathlessness is a prevalent disabling syndrome affecting many people for years. Identifying the impact of chronic breathlessness on people's activities in the general population is pivotal for designing symptom management strategies. Objective: This study aimed to evaluate the association between chronic breathlessness and activities respondents identify can no longer be undertaken (?activities forgone?). Design: This population-based cross-sectional online survey used a market research company's database of 30,000 registrants for each sex, generating the planned sample size?3000 adults reflecting Australia's 2016 Census by sex, age group, state of residence, and rurality. Setting/Subjects: The population of focus (n?=?583) reported a modified Medical Research Council (mMRC) breathlessness scale ?1 and experienced this breathlessness for ?3 months. Measurements: Activities forgone were categorized by mMRC using coding derived from the Dyspnea Management Questionnaire domains. Activities were classified as ?higher/lower intensity? using Human Energy Expenditure scale. Results: Respondents were male 50.3%; median age 50.0 (IQR 29.0); with 66% living in metropolitan areas; reporting 1749 activities forgone. For people with mMRC 1 (n?=?533), 35% had not given up any activity, decreasing to 9% for mMRC 2 (n?=?38) and 3% for mMRC 3?4 (n?=?12). Intense sport (e.g., jogging and bike riding) was the top activity forgone: 42% (mMRC 1), 32% (mMRC 2), and 36% (mMRC 3?4). For respondents with mMRC 3?4, the next most prevalent activities forgone were ?sexual activities? (14%), ?lower intensity sports? (11%), and ?other activities? (11%). Conclusions: People progressively reduce a wide range of activities because of their chronic breathlessness.

Abstract Background Chronic breathlessness is a recognized clinical syndrome that severely impacts patients and carers, who become increasingly restricted in their daily activities. Often, patients become reliant on their carers, who are required to provide constant support. Although individual experiences of breathlessness have been previously investigated, there are few studies exploring contemporaneous experiences of breathlessness of the patient and their carer. This study aimed to understand the experience of severe chronic breathlessness in people with chronic obstructive pulmonary disease (COPD) from the perspective of the patient and carer unit. Methods A qualitative study embedded in a randomised, placebo-controlled effectiveness study (RCT) of regular, low-dose (≤32 mg/day), sustained-release morphine for chronic breathlessness associated with COPD. Recruitment occurred between July 2017 and November 2018 in one respiratory and palliative care services, in South Australia. Participants were community-dwelling patients with COPD and severe breathlessness (modified Medical Research Council scale 3 or 4) and their carers. Separate semi-structured interviews were conducted with patients and carers, recorded and transcribed verbatim. Analysis was informed by grounded theory using a constant comparative approach. Results From the 26 patients with a carer recruited for the RCT in South Australia, nine were interviewed in their homes. Six patients were men, median age 77 years. Carers were mostly women, who were their wives (n = 6), median age 70. Five themes emerged from the data: (1) shrinking world; (2) mutual adaptation; (3) co-management; (4) emotional coping; and (5) meaning in the face of death. Conclusion Chronic breathlessness is a systemic condition that permeates all aspects of the patient’s and carer’s lives. Working as a team, patients and carers manage chronic breathlessness to achieve maximal function and well-being. Patients and carers share many aspects of the experience of breathlessness, but the carer seems particularly susceptible to emotional distress. Future chronic breathlessness interventions should target the patient and the carer, both together and separately to address their common and individual needs. Trial registration The main trial is registered (registration no. NCT02720822 ; posted March 28, 2016).

Lack of access to therapeutic opioids continuing causes global health inequalities. Access to morphine for symptom control is regulated under the terms of the Single Convention on Narcotics, countries must submit annual morphine requirement estimates and report consumption to the International Narcotics Control Board (INCB). INCB indicates access to morphine is increasing, however, estimated needs are unreported so changing proportions of needs feasibly met by requirements and consumption are unknown. Retrospective time series-analysis taking cross-sections every five years of gaps between calculated needs for morphine for people who die from cancer and total treatable using estimates of requirements and consumption (1997, 2002, 2007, 2012, 2017). We calculated need using INCB-recommended methods (80% of people who die from cancer require 67.5mg of morphine daily for 90 days (6.075g)) for countries reporting estimates and consumption using Global Burden of Disease cancer deaths by country. Gaps between calculated need and total treatable population using estimates and consumption were calculated. We report proportions of need feasibly met by estimates and consumption for included countries, by World Bank Income group. Global availability of morphine increased, from estimates sufficient to treat 86% of calculated needs in 1997, to 701% in 2017. However, proportion of countries estimating requirements feasibly meeting >100% of calculated needs rose only from 16% to 30%. Almost all Low-and-Middle-Income Countries submitted inadequate estimates with little change in 20 years. Consumption was lower than calculated needs at all time-points. Very few countries reported consumption greater than their estimate of requirement. Most countries submitted morphine estimates insufficient to meet analgesic needs of people who died from cancer. Estimates of requirements contextualise future Consumption, and increases in adequacy of estimates and consumption were minimal over 20 years. Annual publication of calculated morphine needs alongside estimates and consumption may be a key step to drive countries’ accountabilities.

Abstract Aims Morphine is shown to relieve chronic breathlessness in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost‐effectiveness of 12 weeks morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo. Methods and results Parallel group, double‐blind, randomized, placebo‐controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between‐group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment‐emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39–89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, −0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change‐from‐baseline) but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no between‐group differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise‐related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups but by more in the morphine group [morphine 2169 (1092, 3851) pg/mL vs. placebo 2851 (1694, 5437)] pg/mL. There was no excess serious adverse events in the morphine group. Treatment‐emergent harms during the first week were more common in the morphine group; all apart from 1 were ≤ grade 2. Conclusions We could not answer our primary objectives due to inadequate power. However, we provide novel placebo‐controlled medium‐term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful and with early management of side effects.

Background Most health service utilisation studies are of people with specific diagnoses or demographic characteristics, and rarely of specific chronic symptoms. The aim of this study was to establish whether population-level health service utilisation increases in people with chronic breathlessness. Methods A cross-sectional analysis was carried out of the South Australian Health Omnibus Survey 2017, a multi-stage, clustered area, systematic sampling survey of adults where questions are administered face-to-face in respondents’ homes. Self-report of health service utilisation in the previous 3 months (medical consultations, emergency department, hospital admission), chronic breathlessness (severity, duration, modified Medical Research Council (mMRC) breathlessness scale) and demographic data were used to predict self-reported health service utilisation. Results A total of 2898 people were included (49.0% male; median age 48.0 years (IQR 32.0–63.0); 64.1% educated beyond school; 55.4% in work; 73.5% had outpatient contact; 6.3% had a hospital admission in the previous 3 months). Chronic breathlessness (mMRC ≥1) was reported by 8.8% of respondents. In bivariable analyses, people with greater contact with health services were older, and a higher proportion were overweight/obese and had more severe chronic breathlessness. In multivariable analyses, chronic breathlessness and older age were positively associated with outpatient care and inpatient care, and people with chronic breathlessness were hospitalised for longer (incidence rate ratio 2.5; 95% CI 1.4–4.5). Conclusion There is a significant association between worse chronic breathlessness and increased health service utilisation. There is a need for greater understanding of factors that initiate contact with health services.

Abstract Objective Long-term oxygen therapy (LTOT) during 15 h/day or more prolongs survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxemia. No randomized controlled trial has evaluated the net effects (benefits or harms) from LTOT 24 h/day compared with 15 h/day or the effect in conditions other than COPD. We describe a multicenter, national, phase IV, non-superiority, registry-based, randomized controlled trial (R-RCT) of LTOT prescribed 24 h/day compared with 15 h/day. The primary endpoint is all-cause-mortality at 1 year. Secondary endpoints include cause-specific mortality, hospitalizations, health-related quality of life, symptoms, and outcomes in interstitial lung disease. Methods/design Patients qualifying for LTOT are randomized to LTOT 24 h/day versus 15 h/day during 12 months using the Swedish Register for Respiratory Failure (Swedevox). Planned sample size in this pragmatic study is 2126 randomized patients. Clinical follow-up and concurrent treatments are according to routine clinical practice. Mortality, hospitalizations, and incident diseases are assessed using national Swedish registries with expected complete follow-up. Patient-reported outcomes are assessed using postal questionnaire at 3 and 12 months. Discussion The R-RCT approach combines the advantages of a prospective randomized trial and large clinical national registries for enrollment, allocation, and data collection, with the aim of improving the evidence-based use of LTOT. Trial registration Clinical Trial registered with www.clinicaltrials.gov, Title: REgistry-based Treatment Duration and Mortality in Long-term OXygen Therapy (REDOX); ID: NCT03441204.

Abstract Background The aim of the study was to assess four evidence-based assessments utilising exercise challenges that induce breathlessness, each with progressively less demanding levels of exertion, which can be tailored to people with a range of functional capabilities in the setting of advanced cancer for research studies. Functional cut off points for these assessments have not previously been defined. Methods A cross sectional study of four exercise tests attempted by all participants: 6 min walk test (6MWT); (derived) 2 min walk test (2MWT); arm exercises; and reading numbers aloud. Performance status (Australia-modified Karnofsky Performance Status (AKPS)), baseline breathlessness using the modified Medical Research Council (mMRC) breathlessness scale, and a visual analogue scale of intensity and unpleasantness of breathlessness were measured. Co-morbidity was codified using the Charlson Co-morbidity Index. Percentage of people completing each test by AKPS level of function and baseline mMRC breathlessness scores were quantified. Results In the 68 participants, poorer function decreased the proportion of people able to complete the exercise tests. For completion rates ≥80%, of 6MWT and 2MWT, only people with an AKPS 70–90 had completion. For arm exercises, this included people with an AKPS as low as ≥50; and for reading numbers, it included people with an AKPS of 40 but not below. Conclusions Walking tests have poor utility in people with high levels of functional impairment. For people with high levels of dependence, reading numbers should be used in evaluating exercise-induced breathlessness in research studies. These data also suggest that people’s exertional limitations have been under-estimated as cancer progresses.

Ongoing participation in valued and essential everyday activities remains a priority for people with advanced disease. This study sought to understand factors influencing patients with advanced disease and caregivers’ utilisation of assistive equipment that enable this participation. Employing a pragmatic approach, purposive sampling identified participants who were interviewed in their homes. A semi-structured interview guide was employed to elicit community dwelling patients’ and caregivers’ perspectives about assistive equipment utilisation. Recorded interviews were analysed inductively and themes were constructed from the data. Fourteen interviews were conducted with patients and caregivers. Patients had a range of cancers and COPD. Three empirically developed themes demonstrate the complexities associated with the use of assistive equipment at the end of life: 1. Enabling engagement in everyday activities; 2. Dependency—a two-way street; 3. The pragmatics of choosing, using or declining assistive equipment. Participants were motivated to use assistive equipment when it optimised their function, enabled participation and supported their values, roles and interests. Conversely, use of assistive equipment could be met with ambivalence as it represented deterioration or could cause conflict within relationships. Caregivers found assistive equipment made it easier for them to provide physical care. Skilled proactive assistive equipment prescription and training by allied health professionals enhanced patient and caregiver confidence and capacity to engage in everyday activities.

Breathlessness is common in the general population. Existing data were obtained primarily with the uni-dimensional modified Medical Research Council breathlessness scale (mMRC) that does not assess intensities of unpleasantness nor physical, emotional and affective dimensions. The aim of this research was to determine the prevalence and intensity of these dimensions of breathlessness in elderly males and any associations with their duration, change over time and mMRC grade. We conducted a population-based, cross-sectional study of 73-year-old males in a county in southern Sweden. Breathlessness was self-reported at one time point using a postal survey including the Dyspnea-12 (D-12), the Multidimensional Dyspnea Profile (MDP) and the mMRC. Presence of an increased dimension score was defined as a score ≥minimal clinically important difference for each dimension scale. Association with the mMRC, recalled change since age 65, and duration of breathlessness were analysed with linear regression. Among 907 men, an increased dimension score was present in 17% (D-12 total score), 33% (MDP A1 unpleasantness), 19% (D-12 physical), 17% (MDP immediate perception), 10% (D-12 affective) and 17% (MDP emotional response). The unpleasantness and affective dimensions were strongly associated with mMRC≥3. Higher MDP and D-12 scores were associated with worsening of breathlessness since age 65, and higher MDP A1 unpleasantness was associated with breathlessness of less than 1 year duration. Increased scores of several dimensions of breathlessness are prevalent in 73-year-old males and are positively correlated with mMRC scores, worsening of breathlessness after age 65, and duration of less than 1 year.

Introduction COPD is a major cause of morbidity and mortality. The prevalence, morbidity and mortality of COPD among females have increased. Previous studies indicate a possible gender bias in the diagnosis and management of COPD. The present study aims to determine if there is gender bias in the management of COPD in Sweden. Methods This was a double-blind, randomised (1:1), controlled, parallel-group, web-based trial using the hypothetical case scenario of a former smoker (40 pack-years and quit smoking 3 years ago) who was male or female. The participants were blind to the randomisation and the purpose of the trial. The case progressively revealed more information with associated questions on how the physician would manage the patient. Study participants chose from a list of tests and treatments at each step of the case scenario. Results In total, 134 physicians were randomised to a male (n=62) or a female (n=72) case. There was no difference in initial diagnosis (61 (98%) male cases and 70 (97%) female cases diagnosed with COPD) and planned diagnostic procedures between the male and female cases. Spirometry was chosen by all the physicians as one of the requested diagnostic tests. The management of the hypothetical COPD case did not differ by sex of the responding physician. Conclusion In Sweden, diagnosis and management of a hypothetical patient with COPD did not differ by the gender of the patient or physician.

Chronic breathlessness is a disabling syndrome, prevalent in people with advanced chronic obstructive pulmonary disease (COPD). Regular, low-dose, oral sustained-release morphine is approved in Australia to reduce symptomatic chronic breathlessness. We aimed to determine the current prescribing patterns of opioids for chronic breathlessness in COPD in Australian general practice and to define any associated patient and practitioner characteristics. Five years (2011 to 2016) of the Bettering the Evaluation and Care of Health database, an Australian national, continual, cross-sectional study of clinical care in general practice were used. The database included 100 consecutive clinical encounters from almost 1000 general practitioners annually (n=488 100 encounters). Descriptive analyses with subsequent regression models were generated. Breathlessness as a patient-defined reason for encounter was identified in 621 of 4522 encounters where COPD was managed. Opioids were prescribed in 309 of 4522 encounters where COPD was managed (6.8%; (95% CI) 6.1–7.6), of which only 17 were prescribed for breathlessness, and the rest for other conditions almost entirely related to pain. Patient age (45–64 years versus age 80+ years, OR 1.68; 1.19–2.36), Commonwealth Concession Card holders (OR 1.70; 1.23–2.34) and socioeconomic disadvantage (OR 1.30; 1.01–1.68) were associated with increased likelihood of opioid prescription at COPD encounters. The rate of opioid prescriptions rose over the 5 years of study. In primary care encounters for COPD, opioids were prescribed in 6.8% of cases, but almost never for breathlessness. These data create a baseline against which to compare changes in prescribing as the treatment of chronic breathlessness evolves.

Question addressed by the study Endogenous opioids (endorphins) have been reported to modulate exercise-induced breathlessness, but the relative contribution of peripheral opioid receptors has not been tested. Materials, participants and methods This was a double-blind, randomised, three-arm, cross-over trial in outpatients with spirometry-verified moderate to severe chronic obstructive pulmonary disease. Participants undertook an incremental symptom-limited treadmill test followed by five endurance treadmill tests at 75% of their maximal work rate; two tests for familiarisation and three tests 30 min after intravenous injection of either methylnaltrexone 0.3 mg·kg−1 (blocking peripheral opioid receptors only) or naloxone 0.1 mg·kg−1 (blocking both central and peripheral opioid receptors) or normal saline, in randomised order. The primary end-point was the regression slope between breathlessness intensity (0–10 numerical rating scale) and oxygen consumption (V′O2) during the walk tests, comparing methylnaltrexone and placebo using a paired t-test. Results 17 participants completed the trial: median (range) 66 (55–82) years; 15 males; mean±sd forced expiratory volume (FEV1) 53.8±17.6% predicted; FEV1/forced vital capacity ratio 0.55±15.9. There was no statistically or clinically significant difference in the primary end-point (regression slope of breathlessness intensity and V′O2) for methylnaltrexone (p=0.498) or naloxone (p=0.804), compared to placebo. Secondary outcomes were similar between the three treatment groups, including peak and mean breathlessness intensity and unpleasantness, exercise capacity, endurance time and leg fatigue. Answer to the question Blocking peripheral opioid receptors (methylnaltrexone) or peripheral and central opioid receptors (naloxone) did not appear to modulate breathlessness intensity nor exercise capacity when compared with placebo (no blockade).

Abstract Background Pain is a common and distressing symptom in people with cancer, but is under-recognised and under-treated. Australian guidelines for ‘Cancer Pain Management in Adults’ are available on the Cancer Council Australia Cancer Guideline Wiki. This study aims to evaluate the effectiveness and cost-effectiveness of a suite of guideline implementation strategies for improving pain outcomes in adults with cancer in oncology and palliative care outpatient settings. Methods The study will use a stepped-wedge cluster randomised controlled design, with oncology and palliative care outpatient services as the clusters. Patients will be eligible if they are adults with cancer and pain presenting to participating services during the study period. During an initial control arm, services will routinely screen patients for average and worst pain over the past 24 h using a 0–10 numerical rating scale (NRS) and have unfettered access to online guidelines. During the intervention arm, staff at each service will be encouraged to use: 1) a patient education booklet and self-management resource; 2) an online spaced learning cancer pain education module for clinicians from different disciplines; and 3) audit and feedback of service performance on key indices of cancer pain screening, assessment and management. Service-based clinical change champions will lead implementation of these strategies. The trial’s primary outcome will be the probability that patients initially screened as having moderate-severe (≥5/10 NRS) worst pain experience a clinically important improvement one week later, defined as ≥ 30% reduction. Secondary outcomes will include patient empowerment and quality of life, carer experience, and cost-effectiveness. For the main analysis, linear mixed models will be used, accounting for clustering and the longitudinal design. Eighty-two patients per service at six services (N = 492) will provide > 90% power. A qualitative sub-study and analyses of structural and process factors will explore opportunities for further refinement and tailoring of the intervention. Discussion This pragmatic trial will inform implementation of guidelines across a range of oncology and palliative care outpatient service contexts. If found effective, the implementation strategies will be made freely available on the Wiki alongside the guidelines. Trial registration Registered 23/01/2015 on the Australian New Zealand Clinical Trials Registry (ACTRN12615000064505).

Abstract Background Systemic morphine has evidence to support its use for reducing breathlessness in patients with severe chronic obstructive pulmonary disease (COPD). The effectiveness of the nebulized route, however, has not yet been confirmed. Recent studies have shown that opioid receptors are localized within epithelium of human trachea and large bronchi, a target site for a dosimetric nebulizer. The aim of this study was to compare any clinical or statistical differences in breathlessness intensity between nebulized 2.0% morphine and 0,9% NaCl in patients with very severe COPD. Methods The study was a double-blind, controlled, cross-over trial. Participants received morphine or NaCl during two 4-day periods. Sequence of periods was randomized. The primary outcome measure was reduction of breathlessness intensity now by ≥20 mm using a 100 mm visual analogue scale (VAS) at baseline, 15, 30, 60, 120, 180 and 240 min after daily administration, during normal activities. Results Ten of 11 patients included completed the study protocol. All patients experienced clinically and statistically significant (p

Abstract Background Public concerns are commonly expressed about widening health gaps. This cohort study examines variations and trends in cancer survival by socio-economic disadvantage, geographical remoteness and country of birth in an Australian population over a 30-year period. Methods Data for cases diagnosed in New South Wales (NSW) in 1980–2008 (n = 651,245) were extracted from the population-based NSW Cancer Registry. Competing risk regression models, using the Fine & Gray method, were used for comparative analyses to estimate sub-hazard ratios (SHR) with 95% confidence intervals (CI) among people diagnosed with cancer. Results Increased risk of cancer death was associated with living in the most socio-economically disadvantaged areas compared with the least disadvantaged areas (SHR 1.15, 95% CI 1.13–1.17), and in outer regional/remote areas compared with major cities (SHR 1.05, 95% CI 1.03–1.06). People born outside Australia had a similar or lower risk of cancer death than Australian-born (SHR 0.99, 95% CI 0.98–1.01 and SHR 0.91, 95% CI 0.90–0.92 for people born in other English and non-English speaking countries, respectively). An increasing comparative risk of cancer death was observed over time when comparing the most with the least socio-economically disadvantaged areas (SHR 1.07, 95% CI 1.04–1.10 for 1980–1989; SHR 1.14, 95% CI 1.12–1.17 for 1990–1999; and SHR 1.24, 95% CI 1.21–1.27 for 2000–2008; p

Abstract Background Chronic pain interfering with activities of daily living is highly prevalent in the community. More than 600 million people worldwide are obese. The aim of this paper is to assess if such chronic pain is associated independently with obesity across the adult population, having controlled for other key factors. Methods The South Australian Health Omnibus is an annual, population-based, cross-sectional study. Data on 2616 participants were analysed for episodes of daily pain for three of the preceding six months. Obesity was derived from self-reported height and weight. Multivariable logistic regression analysed the associations between chronic pain interfering with activities of daily living, body mass index (BMI) and key socio-demographic factors. Results Chronic pain interfering with activities of daily living peaks in people ≥75 years of age while obesity peaks in the 45-54 age group. Pain and obesity together peak in the 55-74 year age group. In the adjusted multinominal logistic regression model, compared to those with no pain, there was a strong association between obesity and pain that interfered moderately or extremely with day-to-day activities (OR 2.25; 95 % CI 1.57-3.23; p

Abstract Introduction: Malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) are often grouped together in descriptive epidemiological analyses, resulting in limited understanding of epidemiological patterns for these tumour types. Methods: We studied patterns in the incidence, mortality and survival of people diagnosed with MPM (n=4,076) and MPeM (n=293) in New South Wales (NSW), Australia, 1972–2009. We also calculated 5‐year relative survival for people diagnosed 1972–2006 followed up to 2007. We assessed patterns for each tumour type and histological subtype and, where possible, by combination of these categories. Results: Annual MPM cases steadily increased over time (n=208 in 2009). There was an increasing trend in the MPM age‐standardised incidence rate from 1972 up to 1994. This rate increase has levelled off in the past 10 years. Since 1999, 11 cases of MPeM were diagnosed each year, on average. Five‐year relative survival remained stable for MPM and MPeM. However, 5‐year relative survival in 2002–2006 was substantially higher for people with MPM epithelioid histological subtype (11.7% [95%CI 6.8–18.2%]) compared to all other non‐epithelioid histological subtypes (6.9% [95%CI 5.0–9.1%]), a 70% difference. Survival was also greater for women with MPM (13.4% [95%CI 8.5–19.4%]) compared to men (7.0% [95%CI 5.1–9.2%]). Interpretation: MPM incidence rates have stabilised since the mid‐1990s, suggesting that maximum incidence levels have been reached. When more up‐to‐date data are available, survival estimates should be reanalysed to include people likely to benefit from the wide introduction of combination chemotherapy in 2007, including pemetrexed.

Cancer cachexia is a multilayered syndrome consisting of the interaction between tumor cells and the host, at times modulated by the pharmacologic treatments used for tumor control. Key cellular and soluble mediators, activated because of this interaction, induce metabolic and nutritional alterations. This results in mass and functional changes systemically, and can lead to increased morbidity and reduced length and quality of life. For most solid malignancies, a cure remains an unrealistic goal, and targeting the key mediators is ineffective because of their heterogeneity/redundancy. The most beneficial approach is to target underlying systemic mechanisms, an approach where the novel non-peptide ghrelin analogue anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain. In the ROMANA studies, compared with placebo, anamorelin significantly increased lean body mass in non-small cell lung cancer (NSCLC) patients. Body composition analysis suggested that anamorelin is an active anabolic agent in patients with NSCLC, without the side effects of other anabolic drugs. Anamorelin also induced a significant and meaningful improvement of anorexia/cachexia symptoms. The ROMANA trials have provided unprecedented knowledge, highlighting the therapeutic effects of anamorelin as an initial, but significant, step toward directly managing cancer cachexia.

The goals of all clinical care are based on optimizing a person's comfort and function in physical, emotional, existential, sexual and social domains. Chronic, progressive illnesses generate specific challenges as systemic deterioration shifts the benefit–toxicity balance for the treatment of some long-term comorbid diseases. At every clinical encounter, and especially at times of transition in clinical care (admission to hospital, discharge to the community, a new diagnosis), the opportunity to review the management of comorbid conditions must be taken. This is especially important when a life-limiting illness is first recognized. Careful rationalization of the treatment of chronic comorbid conditions in a systematic way as a person experiences systemic deterioration requires a framework for considering short- and long-term sequelae of both treating and not treating a given condition. The preventative intent of therapy (primary, secondary, tertiary) must be known to make this clinical decision. The numbers needed to treat to avoid one adverse outcome will tend to increase as a person experiences systemic decline and, conversely, the numbers needed to harm will decrease. In addition to reviewing individual medications, consideration must be given to the total burden of prescribing for cumulative effects (e.g., risk of drug–drug interactions, anticholinergic load). Judicious dose reduction or substitution of a more appropriate agent, given the global decline, with continued careful review will allow medications to be titrated to minimize harm at the end of life.

Continuous monitoring and management of a person’s symptoms and performance status are critical for the delivery of effective palliative care. This monitoring occurs routinely in inpatient settings; however, such close evaluation in the community has remained elusive. Patient self-reporting using telehealth offers opportunities to identify symptom escalation and functional decline in real time, and facilitate timely proactive management. We report the case of a 57­year-old man with advanced non-small cell lung cancer who participated in a telehealth trial run by a community palliative care service. This gentleman was able to complete self-reporting of function and symptoms via iPad although at times he was reticent to do so. Self-reporting was perceived as a means to communicate his clinical needs without being a bother to the community palliative care team. He also participated in a videoconference with clinical staff from the community palliative care service and his General Practitioner. Videoconferencing with the nurse and GP was highly valued as an effective way to communicate and also because it eliminated the need for travel. This case report provides important information about the feasibility and acceptability of palliative care telehealth as a way to better manage clinical care in a community setting.