Treatment of agitation in terminally ill patients with intranasal midazolam versus subcutaneous midazolam: study protocol for a randomised controlled open-label monocentric trial (MinTU Study).

BACKGROUND: Intranasal (i.n.) drug application is a widely known and low-invasive route of administration that may be able to achieve rapid symptom control in terminally ill patients. According to the German S3 guideline "Palliative care for patients with incurable cancer", benzodiazepines, such as midazolam, are recommended for the treatment of terminal agitation. To the best of our knowledge there is no evidence for i.n. midazolam in terminally ill patients. We aim to assess the use of i.n. midazolam as an alternative to subcutaneous administration of the drug. METHODS: In this monocentric, randomised, controlled, open-label investigator initiated trial, n = 60 patients treated at the palliative care unit of a University Hospital will be treated with 5 mg midazolam i.n. versus 5 mg subcutaneous (s.c.) midazolam in the control arm when terminal agitation occurs (randomly assigned 1:1). The estimated recruitment period is 18 months. Treatment efficacy is defined as an improvement on the Richmond Agitation Sedation Scale (Palliative Version) (RASS-PAL) and a study specific numeric rating scale (NRS) before and after drug administration. Furthermore, plasma concentration determinations of midazolam will be conducted at t1 = 0 min, t2 = 5 min, and t3 = 20 min using liquid chromatography/mass spectrometry (LC-MS). The primary objective is to demonstrate non-inferiority of midazolam i.n. in comparison to midazolam s.c. for the treatment of agitation in terminally ill patients. DISCUSSION: Midazolam i.n. is expected to achieve at least equivalent reduction of terminal agitation compared to s.c. administration. In addition, plasma concentrations of midazolam i.n. are not expected to be lower than those of midazolam s.c. and the dynamics of the plasma concentration with an earlier increase could be beneficial. TRIAL REGISTRATION: German Clinical Trials Registry DRKS00026775, registered 07.07.2022, Eudra CT No.: 2021-004789-36.

Drug Therapy Safety in Palliative Care-Pharmaceutical Analysis of Medication Processes in Palliative Care.

Pharmacotherapy plays a crucial role in symptom management in palliative care and is associated with risks potentially leading to drug-related problems (DRP). Pharmacists can identify DRPs and advise prescribers on optimizing drug therapy. The aim of this study was to identify DRP in a palliative care unit (PCU) and evaluate corresponding pharmaceutical interventions. A non-randomized before-and-after study in a PCU starts with a control phase, an interphase, and an intervention phase. Primary endpoint: DRP, including pharmaceutical interventions and their acceptance. The medication of all inpatients was recorded at set time points, assessed for potential and manifest DRP, and categorized. In the control phase, the ward pharmacist did not interfere with the clinical team. In the intervention phase, the pharmacist could intervene when a DRP was identified and give recommendations. During the 12-month period, 284 patients were included (control phase n = 138; intervention phase n = 146) and 1079 DRPs were identified (control phase n = 634; intervention phase n = 445). The number of DRPs/patient was significantly reduced by the pharmacist's interventions between the control and intervention phases (4 vs. 3 DRPs, p = 0.001). Overall acceptance of pharmaceutical interventions by prescribers was very high (227/256; 88%). DRPs are hardly preventable. With a clinical pharmacist as a member of the palliative care team, it is possible to reduce the number of DRPs and identify potential problems earlier.

Successful use of Rectal Pregabalin for the Treatment of Chemotherapy-Induced Neuropathic Pain-a Case Report.

INTRODUCTION: A 65-year-old female patient could no longer take oral food or medications due to a duodenal occlusion associated with metastatic urothelial carcinoma. Her pre-existing chemotherapy-induced polyneuropathy had been well treated with pregabalin orally. METHODS: Since only preparations for oral use of pregabalin are available, pregabalin suppositories were compounded by the hospital pharmacy for rectal use in this patient. RESULTS: With the rectal administration, the treatment was successfully continued; we measured a good increase in serum levels and the symptoms improved significantly. DISCUSSION: Cancer patients often need to be treated with co-analgesics. At the end of life, treatment often cannot be continued due to lack of other than oral administration. Our case adds to the low evidence of pregabalin administered rectally.

The impact of the COVID-19 pandemic on processes, resource use and cost in palliative care.

BACKGROUND: The COVID-19 pandemic impacts on working routines and workload of palliative care (PC) teams but information is lacking how resource use and associated hospital costs for PC changed at patient-level during the pandemic. We aim to describe differences in patient characteristics, care processes and resource use in specialist PC (PC unit and PC advisory team) in a university hospital before and during the first pandemic year. METHODS: Retrospective, cross-sectional study using routine data of all patients cared for in a PC unit and a PC advisory team during 10-12/2019 and 10-12/2020. Data included patient characteristics (age, sex, cancer/non-cancer, symptom/problem burden using Integrated Palliative Care Outcome Scale (IPOS)), information on care episode, and labour time calculated in care minutes. Cost calculation with combined top-down bottom-up approach with hospital's cost data from 2019. Descriptive statistics and comparisons between groups using parametric and non-parametric tests. RESULTS: Inclusion of 55/76 patient episodes in 2019/2020 from the PC unit and 135/120 episodes from the PC advisory team, respectively. IPOS scores were lower in 2020 (PCU: 2.0 points; PC advisory team: 3.0 points). The number of completed assessments differed considerably between years (PCU: episode beginning 30.9%/54.0% in 2019/2020; PC advisory team: 47.4%/40.0%). Care episodes were by one day shorter in 2020 in the PC advisory team. Only slight non-significant differences were observed regarding total minutes/day and patient (PCU: 150.0/141.1 min., PC advisory team: 54.2/66.9 min.). Staff minutes showed a significant decrease in minutes spent in direct contact with relatives (PCU: 13.9/7.3 min/day in 2019/2020, PC advisory team: 5.0/3.5 min/day). Costs per patient/day decreased significantly in 2020 compared to 2019 on the PCU (1075 Euro/944 Euro for 2019/2020) and increased significantly for the PC advisory team (161 Euro/200 Euro for 2019/2020). Overhead costs accounted for more than two thirds of total costs. Direct patient cost differed only slightly (PCU: 134.7 Euro/131.1 Euro in 2019/2020, PC advisory team: 54.4 Euro/57.3 Euro). CONCLUSIONS: The pandemic partially impacted on daily work routines, especially on time spent with relatives and palliative care problem assessments. Care processes and quality of care might vary and have different outcomes during a crisis such as the COVID-19 pandemic. Direct costs per patient/day were comparable, regardless of the pandemic.

Rectal use of levetiracetam: best practice report for a stepwise approach for sustainable off-label decision making and treatment.

Off-label drug use is common practice in palliative care. It may pose a risk to the patient and benefit should outweigh harm. A decision and documentation aid for off-label use was developed to support practitioners in clinical practice off-label use. Using the example of the rectal administration of levetiracetam in three patient cases, the utilisation and benefits of the decision and documentation aid are presented and discussed. The rectal administration of levetiracetam clearly is an experimental treatment approach with little underlying evidence. To support and document the decision-making process for or against such an off-label use in clinical practice, it is helpful to have a structured approach in order to make this data comprehensible for a later point in time. Off-label use may be a permissible treatment alternative without underlying evidence, provided it takes place in a well-planned and well-monitored therapeutic setting and the benefits outweigh the potential risks.

[Cannabis in oncology - much ado about nothing?] / Cannabis in der Onkologie ­ viel Rauch um nichts?

The medical use of Cannabis has gained popularity in Europe and Northern America in recent years. Cannabinoids are available as finished pharmaceuticals, flowers and extracts. This article focuses on supportive medicine for oncological patients. Possible indications are pain, chemotherapy-induced nausea and vomiting, loss of appetite and altered taste perception. Despite the enormous cannabis hype in medicine, the evidence for its use in oncology patients is insufficient. However, palliative patients with refractory symptoms could be candidates for a therapeutic trial. The key parameter for choosing a cannabis medicinal product is the THC/CBD ratio. Oral forms of administration are particularly suitable for cannabis-naive and older patients. Mental and cardiovascular side effects should not be underestimated.

Off-label use in adult palliative care - more common than expected. A retrospective chart review.

OBJECTIVE: Off-label drug use seems to be integral to adult palliative care pharmacotherapy. Balancing potential risks and benefits in the context of limited therapeutic options is challenging. To provide specific support for clinicians in dealing with off-label use, it is essential to understand off-label use in everyday clinical practice. The aim of this pilot study was to quantify and describe off-label use in an adult palliative care unit. METHODS: Retrospective chart review of all adult patients treated on a palliative care unit in October 2017. All data on drug use (eg, indication, dose, route of administration) were extracted and matched with the prescribing information. Identified off-label use was subsequently compared with recommendations in the relevant literature. The main outcome measure was frequency and type of off-label drug use. RESULTS: Some 2352 drug application days and 93 drugs were identified for 28 patients. Of all drugs, 47 (51%) were used off-label at least once. Most off-label uses concerned indication (57%) followed by mode of administration. In drugs highly relevant to palliative care the rate of off-label use was as high as 67%. The extent to which off-label therapy was supported by literature was very variable and ranged from 0% to 88%. CONCLUSIONS: These data from a single unit confirm the high prevalence of off-label use in palliative medicine and demonstrate that off-label use in adult palliative care is multifaceted. The data presented allow for a more precise characterisation of various aspects of off-label use in order to derive concrete further measures for research and clinical practice.

Development of a national strategy with recommendations for the care of seriously ill and dying people and their relatives in pandemics: A modified Delphi study.

BACKGROUND: The SARS-CoV-2 pandemic is a constant challenge for health care systems, also in Germany. Care of seriously ill and dying people and their relatives is often neglected and suffering increased due to sub-optimal symptom management, visiting restrictions and lonely dying. The project "Palliative Care in Pandemics (PallPan)" intended to develop a national strategy including evidence- and consensus-based recommendations for the care of seriously ill and dying people and their relatives during pandemic times in Germany. AIM: To reach consensus on evidence-based recommendations for the care of seriously ill and dying people and their relatives in pandemics. METHODS: Three-step consensus process comprising two online Delphi rounds and an expert workshop conducted from April to June 2021. One hundred twenty experts from various areas of healthcare, administration, and politics in Germany were included. RESULTS: During the consensus-process, pre-formulated evidence-based recommendations were refined step-by-step. This resulted in consensus on 33 recommendations on the topics of "supporting patients and their relatives," "supporting staff," and "supporting and maintaining structures and provision of palliative care." The recommendations address professional carers and various responsibilities on a governmental, federal state and municipal level, and in healthcare facilities. CONCLUSION: We provide evidence and consensus-based recommendations for the care of seriously ill and dying people and their relatives in pandemics in Germany. This is an important step towards a pandemic preparedness and hopefully improves the future palliative care response to pandemics.

[Cannabis in oncology - much ado about nothing?] / Cannabis in der Onkologie ­ viel Rauch um nichts?

The medical use of Cannabis has gained popularity in Europe and Northern America in recent years. Cannabinoids are available as finished pharmaceuticals, flowers and extracts. This article focuses on supportive medicine for oncological patients. Possible indications are pain, chemotherapy-induced nausea and vomiting, loss of appetite and altered taste perception. Despite the enormous cannabis hype in medicine, the evidence for its use in oncology patients is insufficient. However, palliative patients with refractory symptoms could be candidates for a therapeutic trial. The key parameter for choosing a cannabis medicinal product is the THC/CBD ratio. Oral forms of administration are particularly suitable for cannabis-naive and older patients. Mental and cardiovascular side effects should not be underestimated.

Sedatives and sedation at the end of life: a nursing home retrospective cohort study.

OBJECTIVES: Sedatives are frequently used at the end of life in specialist palliative care. There is scarce information about their use in nursing homes. Therefore, we aimed to assess the use of (1) sedatives generally and (2) 'sedatives with continuous effect', based on objective operational criteria, within the last week of life in a nursing home. METHODS: This was a retrospective cohort study of residents who died in a German nursing home between 1/2015 and 12/2017, using the nursing home's medical records, which contained drug sheets and nurses' notes. Sedatives analysed were those recommended by guidelines for 'palliative sedation': benzodiazepines, levomepromazine, haloperidol (≥5 mg/day) and propofol. Exploratory statistical analysis was conducted using R V.3.6.1. RESULTS: 46/165 (28%) deceased residents received a sedative during the last week of life, all without use of the term 'sedation'. 26/165 residents (16%) received 'sedatives with continuous effect', for median 4 days (range 1-7). Oral lorazepam was used most frequently, mainly for agitation, anxiety and dyspnoea, but also due to palliative status and patients wish. The median total daily dose of lorazepam within the last week of life was 1.5 mg (range 0.5-7.5). The term 'palliative' was significantly more often used for residents receiving sedatives (p=0.001). CONCLUSIONS: Compared with published data on continuous deep sedation, moderate or deep sedation was less frequent in this nursing home and never labelled as 'sedation'. Multicentre mixed-methods research is needed to gain representative and more detailed data on sedation practices at the end of life in nursing homes.

Drug-Related Problems on a Palliative Care Unit.

Pharmacotherapy is essential in palliative medicine. Besides potential benefits, pharmacotherapy also poses potential risks that need to be minimized for patient safety. Pharmacists can play an important role in identifying, solving, and avoiding drug-related problems (DRPs). The aim of this study was to evaluate pharmaceutical interventions on safety of drug therapy in patients in an inpatient palliative care unit. All patients admitted to a palliative care unit over a 12-month period were screened for eligibility (ie, life expectancy >4 weeks). To identify and assess DRPs, patients' pharmacotherapy was evaluated by a pharmacist according to various aspects (eg, drug selection, dose selection, or treatment duration according to the Pharmaceutical Care Network Europe classification for DRPs). During the 12-month period, 41 patients were included. Patients received a median of 11 (range, 1-22) different drugs. Overall, 207 DRPs were documented (median 5 DRPs/patient). After recording a DRP, the pharmacist directly intervened 290 times in order to solve the DRP, which was successful in 181/207 (88%). Clinically relevant DRPs are common in palliative medicine. The systematic assessment can support therapy decisions. This can result in optimized drug therapy, subsequently having a positive effect on symptom control and quality of life.

[Sedation in palliative care - step by step]. / Sedierung in der Palliativversorgung ­ Schritt für Schritt.

Sedation in palliative care, also called "palliative sedation", is an important treatment option for patients who experience unbearable suffering from treatment-refractory symptoms at the end of life. The aim is to reduce this suffering as far as possible by reduction of the patient's consciousness. Good communication between all people involved is crucial for these clinically and ethically challenging situations. This article presents definitions of key terms and of different types of sedation. It then describes the process of sedation step by step: 0. Pre-emptive discussion of the option of sedation (in the context of advance care planning); 1. indication and decision making; 2. information and informed consent; 3. documentation when starting sedation; 4. start of sedation; 5. monitoring and adaption of sedation; 6. medical and nursing care and documentation during sedation; 7. care and processes after the death of the patient (if applicable).

Drug Information Needs of Health Care Professionals in Palliative Care: A Retrospective Evaluation of a Palliative Care Drug Information Service.

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.

A Systematic Review of Seizure-Freedom Rates in Patients With Benign Epilepsy of Childhood With Centrotemporal Spikes Receiving Antiepileptic Drugs.

OBJECTIVES: The objective of this study was to evaluate seizure remission rates in patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) receiving antiepileptic drugs. METHODS: PubMed and Web of Science were searched for studies on pharmacotherapy in patients with BECTS using free search terms or Medical Subject Headings. Only studies that used seizure-freedom rates as an indicator for pharmaceutical efficacy were considered. Different antiepileptic drugs were compared using the Fisher exact test for seizure-freedom rates. RESULTS: A total of 19 studies were included, 6 of them being randomized controlled trials. The randomized controlled trials included a total of 308 patients and covered sulthiame (n = 52), topiramate (n = 45), levetiracetam (n = 43), oxcarbazepine (n = 31), carbamazepine (n = 68), and clobazam (n = 18) as well as placebo (n = 35) and untreated control groups (n = 16). Treatment success rates were significantly higher in those children treated with sulthiame, levetiracetam, and clobazam compared with the children treated with carbamazepine, oxcarbazepine, or topiramate. CONCLUSIONS: The available literature suggests the use of sulthiame, levetiracetam, or clobazam as first-line agents for the treatment of BECTS.

[Off-label use in palliative medicine]. / "Off label use" in der Palliativmedizin.

Palliative care serves to improve the quality of life in patients suffering from incurable diseases. Pharmacotherapy of distressing symptoms plays an important role. Off-label use refers to the use of drugs outside the marketing authorization. In addition to the indications off-label use may also be due to duration of treatment, route of administration and the admixture of substances. Off-label use is common in palliative and hospice care and is probably unavoidable in many cases. For treatment planning and realization of off-label therapy in clinical practice, patient-related aspects, information, therapy monitoring and documentation of therapy effects should be considered in addition to drug-related information. Only in this way it is possible to offer a scientifically adequate, appropriate and economic therapy that is linked to an appropriate risk-benefit ratio for the individual patient. Due to the lack of authorization studies, reporting is of particular importance.

Off-label drugs in palliative care: a Group Delphi treatment recommendation process.

OBJECTIVES: The use of drugs beyond their marketing authorisation, that is, off-label use, is common practice in palliative care with over 70% of off-label use having little or no scientific support. The lack of evidence makes recommendations for off-label use essential, in order to increase the safety of drug therapy and thus patient safety. The aim of this study was to develop a guide for preparing and consenting drug-specific recommendations for off-label use in palliative care. METHODS: Group Delphi Study with three rounds and a prior online survey to identify topics of dissent. Participants represented professional groups working in palliative care involved in direct patient care and/or drug management and various care settings. Furthermore, representatives of relevant professional associations, experts with academic, non-clinical background and experts with international expertise were invited. RESULTS: 18/20 invited professionals participated in the prior online-survey. 15 experts participated in the Group Delphi process. Six domains, including identification of drugs, drug uses, assessment of evidence, formulation, consensus and updating of recommendations were generated and respective statements were included in the Group Delphi process. The consensus process resulted in 28 statements forming the guide for recommendations. CONCLUSIONS: The resultant systematic approach for preparing and consenting drug-specific recommendations for off-label use will allow the development of recommendations with transparent and reproducible monographs. This will help to increase treatment quality and patient safety as well as security of decision-making in palliative care. The developed guide is part of a larger project aiming to provide therapy recommendations for areas that have little or no scientific evidence.

Sedatives and Sedation at the End of Life in Nursing Homes: A Retrospective Multicenter Cohort Study.

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.

Drug use beyond the licence in palliative care: A systematic review and narrative synthesis.

BACKGROUND: Drug use beyond the licence (off-label use, off-label drug use) is a common practice in palliative care and respective recommendations can often be identified in the literature. It is both risky and offers opportunities at the same time and, therefore, requires special attention in clinical practice. AIM: To determine the prevalence of off-label drug use in palliative care and to identify, evaluate and critically appraise studies describing the clinical practice, healthcare professionals' awareness, knowledge and attitudes towards off-label-use and management strategies. DESIGN: Systematic literature review following the guidance of the Centre for Reviews and Dissemination. DATA SOURCES: Medline, Embase, Web of Science and Current Contents Connect were searched in July 2018 as well as hand searches. The reference lists of pertinent studies were screened for further relevant publications, and citation tracking was performed. RESULTS: Eight studies met the inclusion criteria. Due to the variety in study designs and settings, no meta-analysis or meaningful statistical analysis was possible and a narrative synthesis of the data was performed. Frequency of off-label drug use ranged from 14.5% to 35%. Up to 97% of palliative care units did not have any policy or guidance on handling off-label drug use. About 20% of prescribers never obtain consent in the context of off-label use. CONCLUSION: Off-label use is common in palliative care with up to one-third of prescriptions affected. Challenges are often related to obtaining informed consent. Little is known about the decision-making process. More information and guidance for the prescribers are needed to enable safe handling of drugs outside their licence in palliative care.