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Background: Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine the effectiveness of mirtazapine to alleviate severe persisting breathlessness., Methods: This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per day, tapered at treatment end. Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was worst breathlessness in the preceding 24 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete., Findings: Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group., Interpretation: Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness., Funding: EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731)., Competing Interests: Declaration of interests IJH reports grants from EU, Marie Curie Cancer Care, and National Institute for Health and Care Research (NIHR), and is Scientific Director of Cicely Saunders International, NIHR Emeritus Senior Investigator, and is an Honorary Clinical Consultant in Palliative Medicine for hospitals under Kings College Hospital National Health Service Foundation Trust outside of the submitted work. CEB reports grants from the EU, NIHR, AstraZeneca as well as an industry collaboration and a personal fee from Roche outside of the submitted work. JMBr reports grants from the EU and reports being an uncompensated NIHR Health Technology Assessment Funding Committee Chair outside of the submitted work. DCC reports personal fees from Helsinn Pharmaceuticals, Mayne Pharma International, Nous Group, iCare Dust Disease Board, and an unpaid consultant to Chris O'Brien Lighthouse outside of the submitted work. BF reports grants from the Wellcome Trust and is a member of the Ethics Advisory Board Our Future Health, Assurance Board member Cass Review, EU appointed Ethics Advisor to the River EU project, Advisory Board Member Italian MS ConCure project, Advisory Group for Monash University, and Advisory Panel Member for Economic and Social Research Council outside of the submitted work. SPH reports personal fees from Trevi Therapeutics, Boehringer Ingelheim, Chiesi, and is a Trustee for Action for Pulmonary Fibrosis outside of the submitted work. CB, MJJ, AOO, KR, and STS report grants from the EU. MM reports grants from the EU, UKRI, and NIHR. MK and PJ report grants from the EU and Poland Ministry of Science and Higher Education for participation in Horizon 2020. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The Munich Breathlessness Service (MBS) significantly improved control of breathlessness measured by the Chronic Respiratory Questionnaire (CRQ) Mastery in a randomized controlled fast track trial with waitlist group design spanning 8 weeks in Germany. This study aimed to assess the within-trial cost-effectiveness of MBS from a societal perspective., Methods: Data included generic (5-level version of EQ-5D) health-related quality of life and disease-specific CRQ Mastery. Quality-adjusted life years (QALYs) were calculated based on 5-level version of EQ-5D utilities valued with German time trade-off. Direct medical costs and productivity loss were calculated based on standardized unit costs. Incremental cost-effectiveness ratios (ICER) and cost-effectiveness-acceptance curves were calculated using adjusted mean differences (AMD) in costs (gamma-distributed model) and both effect parameters (Gaussian-distributed model) and performing 1000 simultaneous bootstrap replications. Potential gender differences were investigated in stratified analyses., Results: Between March 2014 and April 2019, 183 eligible patients were enrolled. MBS intervention demonstrated significantly better effects regarding generic (AMD of QALY gains of 0.004, 95% confidence interval [CI] 0.0003 to 0.008) and disease-specific health-related quality of life at nonsignificantly higher costs (AMD of €605 [95% CI -1109 to 2550]). At the end of the intervention, the ICER was €152 433/QALY (95% CI -453 545 to 1 625 903) and €1548/CRQ Mastery point (95% CI -3093 to 10 168). Intervention costs were on average €357 (SD = 132). Gender-specific analyses displayed dominance for MBS in males and higher effects coupled with significantly higher costs in females., Conclusions: Our results show a high ICER for MBS. Considering dominance for MBS in males, implementing MBS on approval within the German health care system should be considered., (Copyright © 2022. Published by Elsevier Inc.)

Context: Sedation is an accepted, but controversially discussed and challenging measure to treat suffering at the end of life. Although most people die in hospitals or nursing homes, little is known how professionals in these settings deal with sedatives and sedation at the end of life., Objectives: To explore 1) challenges regarding use of sedatives and sedation at the end of life in hospitals and nursing homes, and 2) strategies, and supportive measures to meet these challenges, as perceived by nurses and physicians., Methods: Multicenter qualitative interview study. Forty-nine participants: 12 general practitioners and 12 nurses from five nursing homes, 12 physicians, and 13 nurses from five hospital departments (hematology/oncology (n = 2), neurology, geriatrics, gynecology). Semi-structured qualitative interviews. Data analysis guided by framework approach., Results: Perceived challenges relate to three levels of the care situation: individual, interaction with others, and work environment. The main challenge was defining the adequate timing and/or dose. Other challenges, e.g., disagreements regarding indication or legal uncertainties, were highly interrelated, and strongly associated with this major challenge. Reported strategies and supportive measures to address challenges also corresponded to the three interrelated levels. Major named strategies were education and training, joint decision-making within the team and regular discussion with the patient and family. On the level work environment, no implemented strategies, but wishes for change were identified., Conclusion: To meet the identified challenges in a sustainable way and enable continuous improvement of quality of care, best practice recommendations, and other supportive measures have to address all identified levels of challenges., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Drug therapy is an integral part of palliative care but pharmacotherapy can be challenging for health care professionals. Access to information is essential for health care providers to choose the best drug treatment for an individual patient. A drug information service can support health care professionals to obtain appropriate, unbiased information., Objectives: To describe the enquiries to a palliative care drug information service. Objectives are to determine the information needs (including off-label use) of different professional groups and areas of care, to identify subject areas and drug substances for which there is a high need for information., Methods: Retrospective evaluation of all enquiries to a palliative care drug information service within 24 months from July 2017 to June 2019., Results: During the study period, 477 enquiries reached the drug information service, mostly from physicians (59%), followed by pharmacists (31%). Ketamin was the most discussed drug (11%), in general enquiries or corresponding replies mostly contained drugs targeting the nervous system, such as analgesics. Application techniques (26%) was the most relevant category, cancer pain (24%) was the most frequently addressed symptom. About half of the enquiries (48%) dealt with off-label us, regarding an application mode outside the license., Conclusion: The information needs on palliative care pharmacotherapy seem to be particularly high among physicians. The demand for information in the area of application technology is particularly apparent and demonstrates a therapeutic gap in terms of availability of suitable preparations as well as necessary information., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: There is scarce information about sedation in nursing homes at the end of life. We aimed to assess (1) the use of sedatives generally and "sedatives with continuous effect," based on objective operational criteria, within the last week of life in nursing homes and (2) factors associated with this treatment., Design: Retrospective cohort study, using the nursing homes' medical records., Setting and Participants: Residents who died in 4 German nursing homes from January 2015 to December 2017 and whose medical records were available (n = 512)., Methods: Sedatives analyzed were those recommended by guidelines for "palliative sedation": benzodiazepines, levomepromazine, haloperidol (≥5 mg/d), and propofol. The definition of "sedatives with continuous effect" and doses judged as at least moderately sedating were consented by palliative care clinicians and pharmacists, based on the literature. Descriptive statistics and multivariate logistic regression analysis were performed (R version 3.6.1)., Results: Overall, 110/512 (21%) deceased residents received a sedative at least once during the last week of life, 46/512 (9%) "sedatives with continuous effect." Oral lorazepam was used most frequently. Eleven of 512 (2%) residents received doses judged as at least moderately sedating. The term sedation was not used. Most frequent indications were agitation (58/110; 53%) and anxiety (35/110; 32%); no indication was noted for 36/110 (33%) residents. The resident's involvement in the decision for sedatives was documented in 3/110 (3%). Multivariate logistic regression analysis showed significant associations between use of sedatives and age (OR = 0.94, P < .001) as well as institution (P < .001)., Conclusions and Implications: Our data indicate a lower prevalence of sedation compared to international data and considerable differences regarding prevalence between institutions. These differences, potential setting-specific challenges, and need for support measures for consistent best practice of sedation in nursing homes should be further explored., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Dignity is poorly conceptualized and little empirically explored in end-of-life care. A qualitative evaluation of a service offering integrated palliative and respiratory care for patients with advanced disease and refractory breathlessness uncovered an unexpected outcome, it enhanced patients' dignity., Objectives: To analyze what constitutes dignity for people suffering from refractory breathlessness with advanced disease, and its implications for the concept of dignity., Methods: Qualitative study of cross-sectional interviews with 20 patients as part of a Phase III evaluation of a randomized controlled fast-track trial. The interviews were transcribed verbatim, imported into NVivo, and analyzed through constant comparison. The findings were compared with Chochinov et al.'s dignity model. The model was adapted with the themes and subthemes specific to patients suffering from breathlessness., Results: The findings of this study underscore the applicability of the conceptual model of dignity for patients with breathlessness. There were many similarities in themes and subthemes. Differences specifically relevant for patients suffering from severe breathlessness were as follows: 1) physical distress and psychological mechanisms are interlinked with the disability and dependence breathlessness causes, in the illness-related concerns, 2) stigma is an important component of the social dignity inventory, 3) conditions and perspectives need to be present to practice self-care in the dignity-conserving repertoire., Conclusion: Dignity is an integrated concept and can be affected by influences from other areas such as illness-related concerns. The intervention shows that targeting the symptom holistically and equipping patients with the means for self-care realized the outcome of dignity., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Episodic breathlessness causes additional distress to breathless patients with advanced disease, but management is still insufficient and there is a lack of knowledge on effective coping strategies., Objectives: The aim was to explore patients' self-management strategies for episodic breathlessness., Methods: In-depth interviews with patients suffering from episodic breathlessness as a result of chronic heart failure, chronic obstructive pulmonary disease, lung cancer, or motor neuron disease were conducted. Interviews were transcribed verbatim and analyzed guided by the analytic hierarchy of Framework analysis., Results: A total of 51 participants were interviewed (15 chronic heart failure, 14 chronic obstructive pulmonary disease, 13 lung cancer, and nine motor neuron disease; age, mean [SD], 68 [12], 41% women, median Karnofsky index 60%). They described six main strategies for coping with episodes of breathlessness: reduction of physical exertion, cognitive and psychological strategies, breathing techniques and positions, air and oxygen, drugs and medical devices, and environmental and other strategies. Some strategies were used in an opposing way, e.g., concentrating on the breathing vs. distraction from any thoughts of breathlessness or laying down flat vs. standing up and raising hands., Conclusion: Patients used a number of different strategies to cope with episodic breathlessness, adding more detailed understanding of existing strategies for breathlessness. The findings, therefore, may provide a valuable aid for health care providers, affected patients, and their relatives., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Malignant respiratory tract tumors can lead to massive fluid production, known as bronchorrhea. This symptom can be very distressing itself, and it can lead to or aggravate other symptoms such as dyspnea and cough. Pharmacological treatment options have been reported in the literature. However, no systematic evaluation of their effectiveness has been conducted so far., Objectives: To systematically identify, appraise, and evaluate the effectiveness of symptomatic pharmacological treatment of bronchorrhea in malignant disease in palliative care., Methods: A systematic literature review in Medline, Embase, and the Cochrane Database, as well as citation tracking, hand searches of selected journals, and reference lists of retrieved articles, was performed. For the purpose of this review, only symptomatic treatments were considered., Results: No controlled clinical studies could be identified. Twenty of 48 retrieved references were analyzed in detail. These 20 case reports and case series dealt with the symptomatic pharmacological management of bronchorrhea in malignant disease; the other 28 had to be excluded for various reasons. The majority of patients suffered from bronchioloalveolar carcinoma. Reported treatments comprise corticosteroids, macrolide antibiotics, inhaled indomethacin, octreotide, and tyrosine-kinase inhibitors. For some drugs, significant clinical impact on distressing symptoms associated with bronchorrhea was reported., Conclusion: There are only very limited data on the pharmacological management of bronchorrhea in malignant disease. Because of the distressing nature of the symptom, a pragmatic management strategy is essential. This can include promising treatment options reported in the literature but should also take into account availability, individual tolerability, and costs. Further research is needed., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Breathlessness is one of the most distressing symptoms experienced by patients with advanced cancer and noncancer diagnoses alike. Often, severity of breathlessness increases quickly, calling for rapid symptom control. Oral, buccal, and parenteral routes of provider-controlled drug administration have been described. It is unclear whether patient-controlled therapy (PCT) systems would be an additional treatment option., Objectives: To investigate whether intravenous opioid PCT can be an effective therapeutic method to reduce breathlessness in patients with advanced disease. Secondary aims were to study the feasibility and acceptance of opioid PCT in patients with refractory breathlessness., Methods: This was a pilot observational study with 18 inpatients with advanced disease and refractory breathlessness receiving opioid PCT. Breathlessness was measured on a self-reported numeric rating scale. Richmond Agitation Sedation Scale scores, Palliative Performance Scale scores, vital signs, and a self-developed patient satisfaction questionnaire were used for measuring secondary outcomes. Descriptive and interference analyses (Friedman test) and post hoc analyses (Wilcoxon tests and Bonferroni corrections) were performed., Results: Eighteen of 815 patients (advanced cancer; median age = 57.5 years [range 36-81]; 77.8% female) received breathlessness symptom control with opioid PCT; daily morphine equivalent dose at Day 1 was median = 20.3 mg (5.0-49.6 mg); Day 2: 13.0 mg (1.0-78.5 mg); Day 3: 16.0 mg (8.3-47.0 mg). Numeric rating scale of current breathlessness decreased (baseline: median = 5 [range 1-10]; Day 1: median = 4 [range 0-8], P < 0.01; Day 2: median = 4 [range 0-5], P < 0.01). Physiological parameters were stable over time. On Day 3, 12/12 patients confirmed that this mode of application provided relief of breathlessness., Conclusion: Opioid PCT is a feasible and acceptable therapeutic method to reduce refractory breathlessness in palliative care patients., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: The Palliative care Outcome Scale (POS) and the Support Team Assessment Schedule (STAS) are two outcome measures used in palliative care settings to assess palliative concerns, needs, and quality of care., Objectives: This systematic review builds on the findings of a previous review to appraise the use of the POS and STAS since 2010, particularly the context and nature of their use., Methods: MEDLINE, Embase, PsycINFO, British Nursing Index, and CINAHL were searched for studies published between February 2010 and June 2014. Relevant authors were contacted, and reference lists of included studies were searched. Studies reporting validation or the use of the POS or STAS were included, and data on sample population, how the outcome measure was being used, study design, study aim, and results of the study were extracted., Results: Forty-three studies were included (POS n = 35, STAS n = 8). There was an increase in the use of the POS and STAS in Europe and Africa with the publication of 13 new translations of the POS. Most studies focused on the use, rather than further validation, of the POS and STAS. There has been increasing use of these measures within non-cancer patient groups., Conclusion: The POS and STAS are now used in a wide variety of settings and countries. These tools may be used in the future to compare palliative care needs and quality of care across diverse contexts and patient groups., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Patient-centered outcome measures (PCOMs) are an important way of promoting patient-professional communication. However, evidence regarding their implementation in palliative care is limited, as is evidence of the impact on care quality and outcomes., Objectives: The aim was to systematically review evidence on capture and feedback of PCOMs in palliative care populations and determine the effects on processes and outcomes of care., Methods: We searched Medline, Embase, CINAHL, BNI, PsycINFO, and gray literature from 1985 to October 2013 for peer-reviewed articles focusing on collection, transfer, and feedback of PCOMs in palliative care populations. Two researchers independently reviewed all included articles. Review articles, feasibility studies, and those not measuring PCOMs in clinical practice were excluded. We quality assessed articles using modified Edwards criteria and undertook narrative synthesis., Results: One hundred eighty-four articles used 122 different PCOMs in 70,466 patients. Of these, 16 articles corresponding to 13 studies met the full inclusion criteria. Most evidence was from outpatient oncology. There was strong evidence for an impact of PCOMs feedback on processes of care including better symptom recognition, more discussion of quality of life, and increased referrals based on PCOMs reporting. There was evidence of improved emotional and psychological patient outcomes but no effect on overall quality of life or symptom burden., Conclusion: In palliative care populations, PCOMs feedback improves awareness of unmet need and allows professionals to act to address patients' needs. It consequently benefits patients' emotional and psychological quality of life. However, more high-quality evidence is needed in noncancer populations and across a wider range of settings., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Depression is common among patients with advanced disease but often difficult to detect., Objectives: To assess the Palliative care Outcome Scale (POS) (10 items) against the Geriatric Depression Scale (GDS)-10 total score and the Hospital Anxiety and Depression Scale (HADS)-Depression subscale total score and determine if the POS has appropriate items to screen for depression among people with advanced disease., Methods: This was a secondary analysis performed on five studies. Four psychometric properties were assessed: data quality, scaling assumptions, acceptability, and internal consistency (reliability). Receiver operating characteristic (ROC) curves were used to determine the area under the curve. Sensitivity, specificity, positive and negative predictive values, false positive and negative rates, and positive and negative likelihood ratios were computed., Results: The overall sample had 416 patients from Germany and England: 144 had cancer and 267 had nonmalignant conditions. Prevalence of depression across the sample was 17.5%. Floor and ceiling effects were rare. Cronbach's alpha coefficients for POS items 7 and 8 summed, GDS-10 and HADS-Depression items varied: 0.61 (heart failure) and 0.80 (cancer). Two items combined (Item 7-feeling depressed and Item 8-feeling good about yourself) consistently presented the highest area under the ROC curve, ranging from 0.76 (95% CI 0.60, 0.93) (Germany, lung cancer) to 0.97 (95% CI 0.91, 1.0) (heart failure), highest negative predictive value, and lowest false negative rate. For the overall sample, the cutoff 2/3 presented a negative predictive value of 89.4% (95% CI 84.7, 92.8) and false negative rate of 10.6 (95% CI 7.2, 15.3)., Conclusion: POS items 7 and 8 summed are potentially useful to screen for depression in advanced disease populations., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Breathlessness is a common and distressing symptom, which increases in many diseases as they progress and is difficult to manage. We assessed the effectiveness of early palliative care integrated with respiratory services for patients with advanced disease and refractory breathlessness., Methods: In this single-blind randomised trial, we enrolled consecutive adults with refractory breathlessness and advanced disease from three large teaching hospitals and via general practitioners in South London. We randomly allocated (1:1) patients to receive either a breathlessness support service or usual care. Randomisation was computer generated centrally by the independent Clinical Trials Unit in a 1:1 ratio, by minimisation to balance four potential confounders: cancer versus non-cancer, breathlessness severity, presence of an informal caregiver, and ethnicity. The breathlessness support service was a short-term, single point of access service integrating palliative care, respiratory medicine, physiotherapy, and occupational therapy. Research interviewers were masked as to which patients were in the treatment group. Our primary outcome was patient-reported breathlessness mastery, a quality of life domain in the Chronic Respiratory Disease Questionnaire, at 6 weeks. All analyses were by intention to treat. Survival was a safety endpoint. This trial is registered with ClinicalTrials.gov, number NCT01165034., Findings: Between Oct 22, 2010 and Sept 28, 2012, 105 consenting patients were randomly assigned (53 to breathlessness support service and 52 to usual care). 83 of 105 (78%) patients completed the assessment at week 6. Mastery in the breathlessness support service group improved compared with the control (mean difference 0·58, 95% CI 0·01-1·15, p=0·048; effect size 0·44). Sensitivity analysis found similar results. Survival rate from randomisation to 6 months was better in the breathlessness support service group than in the control group (50 of 53 [94%] vs 39 of 52 [75%]) and in overall survival (generalised Wilcoxon 3·90, p=0·048). Survival differences were significant for patients with chronic obstructive pulmonary disease and interstitial lung disease but not cancer., Interpretation: The breathlessness support service improved breathlessness mastery. Our findings provide robust evidence to support the early integration of palliative care for patients with diseases other than cancer and breathlessness as well as those with cancer. The improvement in survival requires further investigation., Funding: UK National Institute for Health Research (NIHR) and Cicely Saunders International., (Copyright © 2014 Higginson et al. Open Access article distributed under the terms of CC BY. Published by .. All rights reserved.)

Context: Breathlessness is a distressing symptom in advanced disease. Understanding its patterns, burden, and palliative care (PC) needs over time is important to improve patients' quality of life., Objectives: To describe and compare the courses of refractory breathlessness, functional status, distress, and PC needs in patients with advanced chronic obstructive pulmonary disease (COPD) or lung cancer (LC) over time., Methods: This was a cohort study of patients with COPD (Stage III/IV) or LC. Data were assessed monthly with up to 12 telephone interviews, using the modified Borg Scale, Karnofsky Performance Status Scale, Distress Thermometer, and Palliative care Outcome Scale as outcomes measures. Descriptive analysis compared all outcomes between COPD and LC at baseline and over time (forward from study entry and backward from death)., Results: A total of 82 patients (50 COPD and 32 LC), mean (SD) age of 67.2 (7.8), and 36% female were included (8 COPD and 23 LC deceased). The patients with COPD perceived higher levels of breathlessness and distress at lower functional status steadily over time. The LC patients' breathlessness, distress, and PC needs increased, whereas functional status decreased toward death. The PC needs were similar between disease groups. Breathlessness was negatively correlated with functional status (COPD=mean r=-0.20, P=0.012; LC=mean r=-0.277, P=0.029) and positively correlated with PC needs in COPD patients (mean r=0.343, P<0.001). Death was significantly predicted by diagnosis (LC: hazard ratio=7.84, P<0.001) and functional status (10% decline: hazard ratio=1.52, P=0.001)., Conclusion: The PC needs of patients with advanced COPD are comparable with LC patients, and breathlessness severity and distress are even higher. The care for COPD patients requires further improvement to address symptom burden and PC needs., (Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Episodic breathlessness is a common and distressing symptom in patients with advanced disease. Still, it is not yet clearly defined., Objectives: The aim of this work was to develop an international definition, categorization, and terminology of episodic breathlessness., Methods: An online Delphi survey was conducted with international breathlessness experts. We used a structured questionnaire to identify specific aspects and reach agreement on a definition, categorization, and terminology (five-point Likert scale). Consensus was defined in advance as ≥70% agreement., Results: Thirty-one of 68 (45.6%), 29 of 67 (43.3%), and 33 of 67 (49.3%) experts responded in the first, second, and third rounds, respectively. Participants were 20-79 years old, about 60% male, and more than 75% rated their own breathlessness expertise as moderate to high. After three rounds, consensus was reached on a definition, categorization, and terminology (84.4%, 96.3%, and 92.9% agreement). The final definition includes general and qualitative aspects of the symptom, for example, time-limited severe worsening of intensity or unpleasantness of breathlessness in the patient's perception. Categories are predictable or unpredictable, depending on whether any triggers can be identified., Conclusion: There is high agreement on clinical and operational aspects of episodic breathlessness in advanced disease among international experts. The consented definition and categorization may serve as a catalyst for clinical and basic research to improve symptom control and patients' quality of life., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: A major barrier to widening and sustaining palliative care service provision is the requirement for better selection and use of outcome measures. Service commissioning is increasingly based on patient, carer, and service outcomes as opposed to service activity., Objectives: To generate recommendations and consensus for research in palliative and end-of-life care on the properties of the best outcome measures, enhancing the validity of proxy-reported data and optimal data collection time points., Methods: An international expert "workshop" was convened and an online consensus survey was undertaken using the MORECare Transparent Expert Consultation to generate recommendations and level of agreement. We focused on three areas: 1) measurement properties, 2) use of proxies, and 3) measurement timing. Data analysis comprised descriptive analysis of aggregate scores and collation of narrative comments., Results: There were 31 workshop attendees; 29 recommendations were included in the online survey, completed by 28 experts. The top three recommendations by area were the following: 1) the properties of the best outcome measures are responsive to change over time and capture clinically important data, 2) to enhance the validity of proxy data requires clear and specific guidelines to aid lay individuals' and/or professionals' completion of proxy measures, and 3) data collection time points need clear identification to establish a baseline., Conclusion: Outcome measurement in palliative and end-of-life care requires the use of psychometrically robust measures that are clinically responsive, with defined data collection time points to establish a baseline and clear administration guidelines to complete proxy measures. To further the field requires clinical imperatives to more closely inform recommendations on outcome measurement., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: Unlike pain, where the concept of breakthrough and background pain has been widely characterized and defined, breathlessness as a symptom has not yet been fully explored and has been rarely categorized., Objectives: To explore patients' experiences and descriptions of breathlessness to categorize breathlessness., Methods: Qualitative study using in-depth interviews with patients suffering from four life-limiting and advanced diseases (chronic heart failure, chronic obstructive pulmonary disease, lung cancer, and motor neuron disease). Interviews were tape-recorded, transcribed verbatim, and analyzed using Framework analysis., Results: A total of 51 participants were interviewed (mean ± SD age 68.2 ± 11.6 years; 30 of 51 male; median Karnofsky 60%; mean ± SD breathlessness intensity 3.2 ± 1.7 of 10). Episodic breathlessness and continuous breathlessness were the main categories, with subcategories of triggered and non-triggered episodic breathlessness and continuous breathlessness for short and long periods. Episodic breathlessness triggered by exertion, non-triggered episodic breathlessness, and continuous breathlessness for a long period ("constant variable") were the most frequent and important categories with a high impact on daily living. Exertional breathlessness occurred in nearly all participants. Participants could differentiate episodic breathlessness (seconds, minutes, or hours) and continuous breathlessness (days, weeks, or months) by time. Episodic breathlessness occurred in isolation or in conjunction with continuous breathlessness., Conclusion: Participants categorize their breathlessness by time and triggers. The categorization needs further verification, similar to that already established in pain, and can be used as a new evidence-based categorization to advance our understanding of this under-researched, yet high impact, symptom to optimize management., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: Although episodic breathlessness (EB) is reported to be highly prevalent in advanced disease, our understanding about it is limited., Objectives: The aim of this study was to systematically review and synthesize the evidence on EB regarding definition, characteristics, and patients' experiences., Methods: Systematic review using searches in six databases, hand search, and personal contacts with authors in the field. Search terms included the combination of "episodic" and "breathlessness" (and synonyms) with five different diseases. Selection criteria included patients with advanced disease and information about EB based on original research. All retrieved studies were reviewed by two independent investigators., Results: Twenty-seven studies (of 7584) were included in this review. Only eight studies explored EB as a primary outcome. EB is poorly defined. It is characterized by high prevalence (81%-85%), high frequency (daily), short duration (often less than 10 minutes), and severe peak intensity. EB either develops without any known trigger or is triggered by physical exertion, emotions, or environmental influences., Conclusion: EB is a common symptom in patients with advanced disease, but information about characteristics and experiences is limited. As there is no common terminology, an agreed definition is needed to foster research to develop effective treatments for EB., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Objectives: European populations are ageing, but data on the associated end-of-life care needs are scarce. This study aimed to analyse population, mortality and place of death (PoD) trends in Germany since 1950, and to project mortality by PoD until 2050., Study Design and Methods: Secondary analysis of national statistics on population, mortality and PoD by age and gender. Future numbers and proportions of deaths by PoD - hospital deaths (HDs) and non-hospital deaths (NHDs) - were based on recent trends (2005-2009). Linear models accounted for the effect of age and gender., Results: The German population increased by 19.0% between 1950 and 2002, and has remained relatively stable ever since. However, it is expected that it will decrease (15.4%) from 2009 to 2050 (from 81.8 to 69.4 million). The annual number of deaths has shown an increasing trend, except for a decrease in 1975-2004. A 26.0% increase is expected from 2009 to 2050 (854,544 to 1,077,000 deaths). Older people (age ≥ 75 years) will account for 87.8% of all deaths in 2050 (64.4% in 2009). The proportion of HDs was stable, with an annual mean of 47.0% (range 44.9-47.8%). The models estimated that most people will continue to die outside of hospital in 2050 (48.6 or 54.1%), and absolute numbers of both HDs and NHDs will increase from 2009 to 2050 [HD: by 20.1 million (30.6%); NHD: by 35.5 million (17.0%)]., Conclusions: Unlike in other industrialized countries, most people in Germany die outside of hospital. The need to plan for growing end-of-life care needs and ageing is urgent in Germany but also applies to the rest of Europe. A joint European policy must inform national strategies., (Copyright © 2012 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

This paper explores the use of selective laser sintering (SLS) for the generation of bone tissue engineering scaffolds from polycaprolactone (PCL) and PCL/tricalcium phosphate (TCP). Different scaffold designs are generated, and assessed from the point of view of manufacturability, porosity and mechanical performance. Large scaffold specimens are produced, with a preferred design, and are assessed through an in vivo study of the critical size bone defect in sheep tibia with subsequent microscopic, histological and mechanical evaluation. Further explorations are performed to generate scaffolds with increasing TCP content. Scaffold fabrication from PCL and PCL/TCP mixtures with up to 50 mass% TCP is shown to be possible. With increasing macroporosity the stiffness of the scaffolds is seen to drop; however, the stiffness can be increased by minor geometrical changes, such as the addition of a cage around the scaffold. In the animal study the selected scaffold for implantation did not perform as well as the TCP control in terms of new bone formation and the resulting mechanical performance of the defect area. A possible cause for this is presented., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Cancer end-of-life care (EoLC) policies assume people want to die at home. We aimed to examine variations in preferences for place of death cross-nationally., Methods: A telephone survey of a random sample of individuals aged ≥16 in England, Flanders, Germany, Italy, the Netherlands, Portugal and Spain. We determined where people would prefer to die if they had a serious illness such as advanced cancer, facilitating circumstances, personal values and experiences of illness, death and dying., Results: Of 9344 participants, between 51% (95% CI: 48% to 54%) in Portugal and 84% (95% CI: 82% to 86%) in the Netherlands would prefer to die at home. Cross-national analysis found there to be an influence of circumstances and values but not of experiences of illness, death and dying. Four factors were associated with a preference for home death in more than one country: younger age up to 70+ (Germany, the Netherlands, Portugal, Spain), increased importance of dying in the preferred place (England, Germany, Portugal, Spain), prioritizing keeping a positive attitude (Germany, Spain) and wanting to involve family in decisions if incapable (Flanders, Portugal)., Conclusions: At least two-thirds of people prefer a home death in all but one country studied. The strong association with personal values suggests keeping home care at the heart of cancer EoLC.

Context: Culture has a profound influence on our understanding of what is appropriate care for patients at the end of life (EoL), but the evidence base is largely nonexistent., Objectives: An international workshop was organized to compile a research agenda for cultural issues in EoL research, and assess challenges and implications of the integration of the culture concept in different contexts., Methods: Participant experts were identified from the expert network established through an Internet-based call for expertise on culture and EoL care and from meetings. The workshop comprised presentations of research priorities from country and disciplinary perspectives, and group discussions. Analysis used all data gathered in the workshop and applied standard qualitative techniques., Results: Thirty experts participated in the workshop and identified the following priorities for cross-cultural research: 1) clarifying the concepts of culture and cultural competence; 2) defining EoL in a context of social and cultural diversity, with a focus on concepts of EoL care and bioethics, experiences of receiving and giving EoL care, and care practices in different settings; and 3) developing appropriate methodologies and outcome measurements that address diversity., Conclusion: This first pan-European meeting compiled a research agenda, identifying key areas for future research focusing on culture, diversity, and their operationalization. This requires international and multidisciplinary collaboration, which is necessary in the current efforts to synthesize best practices in EoL care., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Objective: Recent legal changes in Germany make non-compliance with advance directives (ADs) a criminal offence. This article assesses the evidence on attitudes towards, use of, and physician compliance with ADs in Germany., Methods: Critical review: studies on ADs, identified from a systematic review of culture and end-of-life care in Germany (11 electronic databases, 3 journals, reference lists, and grey literature), were included. An interpretative synthesis of findings revealed cross-cutting themes., Results: Thirty-two studies (1996-2009) were identified. Key themes were: awareness; utilization; compliance; and bindingness of ADs. There was a positive trend between awareness of ADs and study publication date. Use varied between patient groups (0.3-62%) and was low amongst the general population (2.5-10%). Fears about ADs' purpose and possible abuse were identified. Physician discomfort in discussing ADs and non-compliance were reported. Physicians preferred legally binding ADs, though conflicting results were reported for patients' desired level of bindingness., Conclusion: Although there is increasing awareness of ADs in Germany, there remains low use, poor communication, fears of abuse, some non-compliance and contradictory evidence regarding desired bindingness., Practical Implications: Although legal changes will hopefully improve compliance, low awareness, communication difficulties and uncertainties surrounding ADs must be addressed if use is to increase., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Context: As the European population ages and the number of cancer deaths annually increases, there is an urgent requirement to provide high-quality, effective care. The measurement of outcomes in advanced disease is complex, and to conduct comparative research and meta-analyses, appropriate tool selection is essential., Objectives: This study aimed to identify the outcome tools currently in use in end-of-life care (both clinically and for research) across Europe and investigate the preferred features of outcome tools from the perspective of those who select and apply them., Methods: A pan-European Internet-based survey of tool users was conducted in research and clinical populations. Respondents were asked to identify the tools they are using and describe ideal features of the measures. The study was conducted in accordance with guidance for best practice in web-based research., Results: Of the 311 participants who completed a survey, 99 tools in clinical care and audit, and 94 in research, were cited by less than 10 participants. Further data revealed that respondents require the number of potential tools to be rationalized and that brief tools are favored., Conclusion: The selection of valid and appropriate tools for palliative care populations requires expert guidance and support to ensure that clinicians and researchers are collecting data that have validity and potential for comparison within and between populations and countries., (Copyright © 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Background: There is a plethora of assessment tools available to measure breathlessness, the most common and disabling symptom of advanced cardio-respiratory disease. The aim of this systematic review was to identify all measures available via standard search techniques and review their usefulness for patients with advanced disease., Methods: A systematic literature search was performed in Medline. All studies focusing on the development or evaluation of tools for measuring breathlessness in chronic respiratory disease, cardiac disease, cancer, or MND were identified. Their characteristics with regard to validity, reliability, appropriateness and responsiveness to change were described. The tools were then examined for their usefulness in measuring significant aspects of breathlessness in advanced disease., Results: Thirty-five tools were initially identified, two were excluded. Twenty-nine were multidimensional of which 11 were breathlessness-specific and 18 disease-specific. Four tools were unidimensional, measuring the severity of breathlessness. The majority of disease-specific scales were validated for chronic obstructive pulmonary disease (COPD), few were applicable in other conditions. No one tool assessed all the dimensions of this complex symptom, which affects the psychology and social functioning of the affected individual and their family--most focused on physical activity., Conclusion: As yet there is no one scale that can accurately reflect the far-reaching effects of breathlessness on the patient with advanced disease and their family. Therefore, at present, we would recommend combining a unidimensional scale (e.g. VAS) with a disease-specific scale (where available) or a multidimensional scale in conjunction with other methods (such as qualitative techniques) to gauge psychosocial and carer distress for the assessment of breathlessness in advanced disease.

The Palliative Care Outcome Scale (POS) is a multidimensional instrument covering physical, psychosocial, spiritual, organizational, and practical concerns. This study validated the German version of the POS and used the tool in different palliative care settings in Germany and Austria. Patients and staff were asked to complete the POS three times and evaluate the questionnaire and the translation afterwards. One hundred eighteen patients (44 male, 74 female, mean age 63 years, all suffering from advanced cancer) completed the POS one time, 55 patients two times, and 36 patients three times. Spearman's rho was highly significant for pain, other symptoms, anxiety, and life worthwhile in the first two assessments. The third assessment showed significant correlations for pain, other symptoms, anxiety, and family anxiety. Seventy-seven of 87 patients answered questions regarding the scale and the translation. All questions other than "Over the past 3 days, have you felt good about yourself?" were understandable for patients. Almost half of the staff was undecided whether the tool was reflecting the patients' condition. In contrast, the majority of patients liked it. Thus, the German version of the POS is well accepted by patients and staff and appears to be valid, although there are some areas where the scale would benefit from expansion to more closely capture staff and patient concerns.