No excess harms from sustained-release morphine: A randomised placebo-controlled trial in chronic breathlessness

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Objectives: We aimed to identify and evaluate: (1) treatment-emergent adverse events (TEAE (worse or new since baseline)) and the subgroup of severe TEAEs in a placebo-controlled 7-day randomised trial of regular, low-dose, sustained-release oral morphine for chronic breathlessness and (2) clinical characteristics associated with TEAE. Methods: Safety analysis of trial data. Adults with chronic breathlessness (modified Medical Research Council breathlessness score ≥2) due to heart or lung disease, or cancer, not on regular opioids were eligible. Symptoms associated with opioids (TEAE of special interest) were systematically sought using Common Terminology Criteria for Adverse Events (CTCAE) grading. Other harms could be reported at any time. The relationship between characteristics and presence of ≥1 TEAE of special interest was explored using univariable logistic regression analyses. Results: 1449/5624 (26%) Adverse Events from 279 participants were TEAE of which 150/1449 (10%) were severe (CTCAE grades 3-5). 1086/5624 (75%) were events of special interest of which 41/1086 (4%) were severe. Compared with placebo, morphine was not associated with more TEAE or severe TEAE of special interest (TEAE: OR 0.53, 95% CI 0.21 to 1.38, p=0.20; severe TEAE: OR 0.96, 95% CI 0.27 to 3.41, p=0.95) nor with CTCAE severity grade (χ2=4.39, p=0.50). Among the 26/150 (17%) with severe TEAEs, study withdrawal was more common in the morphine arm (18/26 (69%) morphine arm; 8/26 (30%) placebo arm). None of the severe TEAEs was a respiratory harm. Conclusions: Severe morphine-associated toxicity was uncommon and not associated with study arm. Clinical consequences were minor and self-limiting. Trial registration number: ACTRN126000806268

End-of-life research: do we need to build proxy consent into all clinical trial protocols studying the terminal phase?

Research into symptoms that occur at the end of life is paramount for ensuring we provide the best possible care for patients in the terminal phase, yet obtaining informed consent from the study participant is not possible at the time these symptoms occur. Importantly, these questions cannot be answered in any clinical population and defining the net clinical effect of medications used, for example, for noisy respiratory secretions is crucial if the quality of care is to be further improved

Progressing an evidence-base beyond case series

High-quality randomized trials in hospice and palliative care are achievable to provide quality evidence to guide our practice especially if several sites work together to conduct the trial. Palliative medicine is a specialty that is contributing more and more to the care of patients with life limiting disease. It is time we based this practice on highquality evidence and that can only come with high-quality research

Toward best practice methods for delirium biomarker studies: An international modified Delphi study

Background: Delirium is a serious and distressing neurocognitive condition common in people with advanced illness. The understanding of delirium pathophysiology is limited and largely hypothetical. To accelerate empirical understanding of delirium pathophysiology, robust scientific methods for conducting and reporting delirium biomarker studies are urgently needed. The aim of this study was to develop international consensus on the core elements of high‐quality delirium biomarker studies. Methods: A three‐round modified Delphi survey was conducted from February to August 2019. Participants were international researchers experienced in conducting delirium studies from a range of settings (hospital, university, research centres). Round one commenced with open‐ended questions developed from results from a prior systematic review and the REMARK (REporting recommendations for tumour MARKer prognostic studies) checklist. Responses were qualitatively analysed, and closed statements were developed. Participants then ranked the importance of these statements using a 5‐point Likert scale in rounds 2 and 3. A priori consensus was defined as ≥70% participant agreement. Descriptive statistics for each item were computed including the mean Likert scores, SD and median participant scores. Results: Twenty-eight participants completed survey round one, 16 completed round two and 19 completed the final round. Consensus was achieved for a total of 60 items. Conclusion: The Delphi survey identified items that expert researchers agreed were important in the conduct of delirium biomarker studies. These reporting items provide a strong platform for improved methodological quality and opportunities to synthesise future delirium biomarker studies

Palliative care nurses\u27 recognition and assessment of delirium symptoms: A qualitative study using critical incident technique

Delirium is prevalent in palliative care inpatient settings and management is often challenging. Despite nurses’ integral patient care role, little is known about palliative care nurses’ capacity to recognise, assess and respond to patients’ delirium symptoms. Objective: To explore the experiences, views and practices of inpatient palliative care nurses in delirium recognition and assessment. Settings and participants: 30 nurses from nine Australian specialist palliative care inpatient services. Design and methods: Critical incident technique (CIT) guided a series of semi-structured interviews. Prior to interviews participants were given a vignette of a palliative care inpatient with an unrecognised hypoactive delirium, to prompt their recollection and recounting of a similar clinical incident. Clearly recalled and described incidents were analysed using thematic content analysis. Findings: 20 of 30 participants recalled and described 28 relevant delirium incidents. Two themes and six sub-themes provide a general description of participants’ experiences, views and practice in delirium recognition and assessment. Participants experience distress related to caring for patients with delirium and express compassion and empathy for delirious patients. Enhancing their delirium knowledge, strengthening collaborative multidisciplinary team relationships and better communication are important supports. Some participants, usually those in advance practice roles, describe more comprehensive assessment capabilities that incorporate clinical expertise with whole person awareness, yet systematic and structured delirium screening and assessment processes and application of the delirium diagnosis criteria are largely missing. Use of ambiguous terminology to describe delirium symptoms contributes to ineffective practice

A collateral benefit of research in palliative care

A collateral benefit of being in a research-active clinical unit is that there is evidence that better care is delivered. The most dramatic data to date demonstrate that in cardiology, research- active cardiology departments in community and university hospitals deliver better survival than those units that do not enroll people in clinical trials

Informed consent in palliative care clinical trials: challenging but possible

Obtaining informed consent is a key protection that should be afforded universally to people using health services and the basis around which any participation in clinical trials is built. Randomized controlled effectiveness studies are necessary to answer key questions in hospice and palliative care, in order to help systematically improve the quality of care. In order to be properly generalizable, such trials need to have broad inclusion criteria to reflect the population most likely to be affected by the condition. The inclusion of patients who are seriously ill, and therefore potentially vulnerable, requires careful exploration of ethical and legal principles that underpin informed consent. Specific challenges in obtaining informed consent for randomised clinical trials (RCTs) in clinically unstable populations such as hospice and palliative care include higher rates of people with impaired cognitive capacity as well as interventional studies in clinical situations which may present as a sudden change in condition. None of these challenges is unique to hospice and palliative care research, but the combination and frequency with which they are encountered require systematic and considered solutions. This article outlines five different ethically valid consent approaches and discusses their applicability to hospice and palliative care research trials. These include: consent by the patient (at the time of enrolment, in advance of the study, or delayed until after the study has commenced); a proxy (or legally authorised representative); or a consent waiver. Increased use of the less traditional modes of informed consent may lead to greater participation rates in hospice and palliative care trials, thereby improving the evidence base more rapidly in part by better reflecting the population served and hence improving generalizability

The clinical and social dimensions of prescribing palliative home oxygen for refractory dyspnea

Background: Chronic breathlessness is a significant problem in palliative care and oxygen is often prescribed in an attempt to ameliorate it. Often, this prescription falls outside the current funding guidelines for long-term home oxygen use. The aim of this qualitative study was to understand the factors that most influence Australian specialist palliative care nurses\u27 initiation of home oxygen for their patients. Methods: A series of focus groups were held across three states in Australia in 2011 involving specialist palliative care nurses. The invitation to the nurses was sent by e-mail through their national association. Recorded and transcribed data were coded for themes and subthemes. A summary, which included quotes, was provided to participants to confirm. Results: Fifty-one experienced palliative care nurses participated in seven focus groups held in three capital cities. Two major themes were identified: 1) logistic/health service issues (not reported in this paper as specific to the Australian context) involving the local context of prescribing and, 2) clinical care issues that involved assessing the patient\u27s need for home oxygen and ongoing monitoring concerns. Palliative care nurses involved in initiating or prescribing oxygen often reported using oxygen as a second-line treatment after other interventions had been trialed and these had not provided sufficient symptomatic benefit. Safety issues were a universal concern and a person living alone did not emerge as a specific issue among the nurses interviewed. Conclusion: The role of oxygen is currently seen as a second-line therapy in refractory dyspnea by specialist palliative care nurses

Anti-cholinergic load, health care utilization, and survival in people with advanced cancer: a pilot study

Introduction: Anti-cholinergic medications have been associated with increased risks of cognitive impairment, premature mortality and increased risk of hospitalisation. Anti-cholinergic load associated with medication increases as death approaches in those with advanced cancer, yet little is known about associated adverse outcomes in this setting. Methods: A substudy of 112 participants in a randomised control trial who had cancer and an Australia modified Karnofsky Performance Scale (AKPS) score (AKPS) of 60 or above, explored survival and health service utilisation; with anti-cholinergic load calculated using the Clinician Rated Anti-cholinergic Scale (modified version) longitudinally to death. A standardised starting point for prospectively calculating survival was an AKPS of 60 or above. Results: Baseline entry to the sub-study was a mean 62 ± 81 days (median 37, range 1–588) days before death (survival), with mean of 4.8 (median 3, SD 4.18, range 1 – 24) study assessments in this time period. Participants spent 22% of time as an inpatient. There was no significant association between anti-cholinergic score and time spent as an inpatient (adjusted for survival time) (p = 0.94); or survival time. Discussion: No association between anti-cholinergic load and survival or time spent as an inpatient was seen. Future studies need to include cognitively impaired populations where the risks of symptomatic deterioration may be more substantial

Delirium management by palliative medicine specialists: a survey from the association for palliative medicine of Great Britain and Ireland

Objectives Delirium is common in palliative care settings. Management includes detection, treatment of cause(s), non-pharmacological interventions and family support; strategies which are supported with varying levels of evidence. Emerging evidence suggests that antipsychotic use should be minimised in managing mild to moderate severity delirium, but the integration of this evidence into clinical practice is unknown.Methods A 21-question online anonymous survey was emailed to Association for Palliative Medicine members in current clinical practice (n=859), asking about delirium assessment, management and research priorities.Results Response rate was 39%: 70% of respondents were palliative medicine consultants. Delirium guidelines were used by some: 42% used local guidelines but 38% used none. On inpatient admission, 59% never use a delirium screening tool. Respondents would use non-pharmacological interventions to manage delirium, either alone (39%) or with an antipsychotic (58%). Most respondents (91%) would prescribe an antipsychotic and 6% a benzodiazepine, for distressing hallucinations unresponsive to non-pharmacological measures. Inpatient (57%) and community teams (60%) do not formally support family carers. Research priorities were delirium prevention, management and prediction of reversibility.Conclusion This survey of UK and Irish Palliative Medicine specialists shows that delirium screening at inpatient admission is suboptimal. Most specialists continue to use antipsychotics in combination with non-pharmacological interventions to manage delirium. More support for family carers should be routinely provided by clinical teams. Further rigorously designed clinical trials are urgently needed in view of management variability, emerging evidence and perceived priorities for research