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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.)

Context: Evidence of symptom control outcomes in severe COVID is scant., Objectives: To determine changes in symptoms among people severely ill or dying with COVID supported by palliative care, and associations with treatments and survival., Methods: Multicentre cohort study of people with COVID across England and Wales supported by palliative care services, during the pandemic in 2020 and 2021. We analysed clinical, demographic and survival data, symptom severity at baseline (referral to palliative care, first COVID assessment) and at three follow-up assessments using the Integrated Palliative care Outcome Scale - COVID version., Results: We included 572 patients from 25 services, mostly hospital support teams; 496 (87%) were newly referred to palliative care with COVID, 75 (13%) were already supported by palliative care when they contracted COVID. At baseline, patients had a mean of 2.4 co-morbidities, mean age 77 years, a mean of five symptoms, and were often bedfast or semiconscious. The most prevalent symptoms were: breathlessness, weakness/lack of energy, drowsiness, anxiety, agitation, confusion/delirium, and pain. Median time in palliative care was 46 hours; 77% of patients died. During palliative care, breathlessness, agitation, anxiety, delirium, cough, fever, pain, sore/dry mouth and nausea improved; drowsiness became worse. Common treatments were low dose morphine and midazolam. Having moderate to severe breathlessness, agitation and multimorbidity were associated with shorter survival., Conclusion: Symptoms of COVID quickly improved during palliative care. Breathlessness, agitation and multimorbidity could be used as triggers for timelier referral, and symptom guidance for wider specialities should build on treatments identified in this study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Systematic data on the care of people dying with COVID-19 are scarce., Objectives: To understand the response of and challenges faced by palliative care services during the COVID-19 pandemic, and identify associated factors., Methods: We surveyed palliative care and hospice services, contacted via relevant organizations. Multivariable logistic regression identified associations with challenges. Content analysis explored free text responses., Results: A total of 458 services responded; 277 UK, 85 rest of Europe, 95 rest of the world; 81% cared for patients with suspected or confirmed COVID-19, 77% had staff with suspected or confirmed COVID-19; 48% reported shortages of Personal Protective Equipment (PPE), 40% staff shortages, 24% medicines shortages, 14% shortages of other equipment. Services provided direct care and education in symptom management and communication; 91% changed how they worked. Care often shifted to increased community and hospital care, with fewer admissions to inpatient palliative care units. Factors associated with increased odds of PPE shortages were: charity rather than public management (OR 3.07, 95% CI 1.81-5.20), inpatient palliative care unit rather than other settings (OR 2.34, 95% CI 1.46-3.75). Being outside the UK was associated with lower odds of staff shortages (OR 0.44, 95% CI 0.26-0.76). Staff described increased workload, concerns for their colleagues who were ill, whilst expending time struggling to get essential equipment and medicines, perceiving they were not a front-line service., Conclusion: Palliative care services were often overwhelmed, yet felt ignored in the COVID-19 response. Palliative care needs better integration with health care systems when planning and responding to future epidemics/pandemics., Competing Interests: Conflict of Interest IJH is a National Institute for Health Research (NIHR) Emeritus Senior Investigator and is supported by the NIHR Applied Research Collaboration (ARC) South London (SL) at King's College Hospital National Health Service Foundation Trust. IJH leads the Palliative and End of Life Care theme of the NIHR ARC SL and co-leads the national theme in this. MM is funded by a NIHR Career Development Fellowship (CDF-2017-10-009) and NIHR ARC SL. LF is funded by a NIHR Career Development Fellowship (CDF-2018-11-ST2-002). KS is funded by a NIHR Clinician Scientist Fellowship (CS-2015-15-005). RC is funded by Cicely Saunders International. FEM is a NIHR Senior Investigator. MBH is supported by the NIHR ARC SL. The views expressed in this article are those of the authors and not necessarily those of the NIHR, or the Department of Health and Social Care., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Palliative care should be a component of COVID-19 management to relieve suffering, improve patient outcomes and save cost., Objectives: We aimed to identify and critically appraise the palliative care recommendations within COVID-19 case management guidelines in African countries., Methods: The study employed systematic guideline review design. All guidelines from any country in Africa, of any language, published between December 2019 and June 2020 were retrieved through online search and email to in-country key contacts. We conducted a content analysis of the palliative care recommendations within the guidelines and appraised the recommendations using African Palliative Care Association standards for providing quality palliative care., Results: We retrieved documents from 29 of 54 African countries. Fifteen documents from 15 countries were included in the final analysis, of which eight countries have identifiable PC recommendations in their COVID-19 management guidelines. Of these eight, only one country (South Sudan) provided comprehensive palliative care recommendations covering the domains of physical, psychological, social and spiritual wellbeing, two (Namibia and Uganda) addressed only physical and psychological wellbeing while the remaining five countries addressed only physical symptom management., Conclusions: Comprehensive palliative care which addresses physical, psychological, social and spiritual concerns must be prioritized within case management guidelines in African countries., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)