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Patients with a limited life expectancy use many medications, some of which may be questionable.Objectives To identify possible solutions for difficulties concerning medication management and formulate recommendations to improve medication management at the end of life.Methods A two-round Delphi study with experts in the field of medication management and end-of-life care (based on ranking in the citation index in Web of Science and relevant publications). We developed a questionnaire with 58 possible solutions for problems regarding medication management at the end of life that were identified in previously performed studies.Results A total of 42 experts from 13 countries participated. Response rate in the first round was 93%, mean agreement between experts for all solutions was 87 % (range 62%–100%); additional suggestions were given by 51%. The response rate in the second round was 74%. Awareness, education and timely communication about medication management came forward as top priorities for guidelines. In addition, solutions considered crucial by many of the experts were development of a list of inappropriate medications at the end of life and incorporation of recommendations for end-of-life medication management in disease-specific guidelines.Conclusions In this international Delphi study, experts reached a high level of consensus on recommendations to improve medication management in end-of-life care. These findings may contribute to the development of clinical practice guidelines for medication management in end-of-life care.

ObjectiveProvide insight in the prevalence of symptoms in patients who are in the last days of life.MethodsA retrospective descriptive analysis of data on patients who died between 2012 and 2019 at the age of 18 or older in 1 of 20 Dutch healthcare facilities, including hospitals, inpatient hospices and long-term care facilities. We analysed data from 4 hourly registrations in the Care Programme for the Dying Person, to assess for how many patients symptom-related goals of care were not achieved. We looked at the first 4 hours episode after the start of the Care Programme and the last 4 hours episode prior to death.ResultsWe analysed records of 2786 patients. In the first 4 hours episode, at least one symptom-related care goal was not achieved for 28.5%–42.8% of patients, depending on the care setting. In the last 4 hours episode, these percentages were 17.5%–26.9%. Care goals concerning pain and restlessness were most often not achieved: percentages varied from 7.3% to 20.9% for pain and from 9.3% to 21.9% for restlessness.ConclusionsSymptom control at the end of life is not optimal in a substantial minority of patients. Systematic assessment and attention as well as further research on symptom management are of the essence.

ObjectivesAt the end of life oral fluid intake is often reduced. Consensus about the most appropriate management for terminally ill patients with limited oral fluid intake is lacking. The objective of this study is to investigate to what extent the amount of fluid intake, preceding and during the dying phase, is related to the occurrence of death rattle and terminal restlessness.MethodsA multicentre prospective observational study was performed. Data on the occurrence of death rattle and terminal restlessness, fluid intake and opioid use of patients expected to die within a few days or hours were collected.Results371 patients were included. Death rattle was reported at least once in 40% (n=149) of patients during the dying phase. Death rattle occurrence was not associated with the amount of fluid intake during the days before dying. Terminal restlessness was reported in 26% of patients (n=96). Terminal restlessness was not associated with a lower amount of fluid intake during the days before dying. Terminal restlessness during the last 24 hours of life was associated with a higher amount of fluid (ie, >250 mL/day) during 48–25 hours before death.ConclusionsCaution with fluid intake to prevent development of death rattle does not seem to be necessary. Our study suggests that a higher amount of fluid intake during 48–25 hours before death may be associated with the occurrence of terminal restlessness during the last 24 hours of life. These results suggest that actively providing dying patients with artificial fluid may not be beneficial.

Objective(s):Unmet needs of relatives of patients with advanced cancer not only reduce their own health-related quality of life, but may also negatively affect patients’ health outcomes. The aim of this study was to assess changes in relatives’ unmet needs of patients with advanced cancer in the last year of life and to identify differences in unmet needs by gender and type of relationship. Methods:Relatives of patients with advanced cancer in the Netherlands were included in a prospective, longitudinal, observational study. Relatives’ unmet needs were measured every 3 months with an adapted version of the Problems and Needs in Palliative Care (PNPC) questionnaire Caregiver form (44 items, 12 domains). Questionnaires completed in the patients’ last year of life were analyzed. Change of unmet needs in the last year, and differences in unmet needs by gender and type of relationship were analyzed. Results:A total of 409 relatives were included with a median of 4 unmet needs in the patient's last year. Unmet needs were most prevalent at all time points during the last year in the domains “caring for the patient” (highest need = 35%) and “psychological issues” (highest need = 40%). The number of unmet needs of relatives did not change significantly during the last year of life (P=.807). There were no significant differences in the number of unmet needs between male and female partners and between partners and other relatives. Conclusion:The most unmet needs for relatives were in the domains “caring for the patient” and “psychological issues.” Professional support should focus on these items. Within these domains, it seems especially important that relatives get more knowledge and support about what scenarios to expect and how to deal with them.

ObjectivesBurdensome and futile interventions with the aim of prolonging life should be avoided in dying patients. However, current clinical practice has hardly been investigated.We examined the number and type of diagnostic and therapeutic medical interventions in hospitalised patients with cancer in their last days of life. In addition, we investigated if physician awareness of impending death affected the use of these interventions.MethodsQuestionnaire study and medical record study. Attending physicians of patients who died in a university hospital between January 2010 and June 2012 were asked whether they had been aware of the patient’s impending death. The use of diagnostic and therapeutic interventions and medications was assessed by studying patients’ charts. We included 131 patients.ResultsIn the last 72 and 24 hours of life, 59% and 24% of the patients received one or more diagnostic interventions, respectively. Therapeutic interventions were provided to 47% and 31%. In the last 24 hours of life, patients received on average 5.8 types of medication.Awareness of a patient’s impending death was associated with a significant lower use of diagnostic interventions (48% vs 69% in the last 72 hours; 11% vs 37% in the last 24 hours) and several medications that potentially prolong life (eg, antibiotics and cardiovascular medication).ConclusionsMany patients with cancer who die in hospital receive diagnostic and therapeutic interventions in the last days of life of which their advantages are questionable. To improve end-of-life care, medical care should be adapted.

Background:Decreasing oral intake is common towards the end of life and a potential source of distress and concern for patients, relatives, whānau and clinicians. This paper provides insight to inform practice regarding clinicians' perceptions, practices, responses and communication with patients and their companions regarding declining oral intake towards the end of life.Methods:In this qualitative study ten specialist palliative care staff participated in semi-structured interviews. Qualitative thematic analysis was used to analyse the data.Findings:Three themes were identified: declining oral intake was a natural part of the dying process; responding empathetically; and clinicians described specific aims and ways regarding communication.Conclusion:Insight into clinicians' endeavours to manage declining oral intake and support the wellbeing of patients, families, and whānau can inform practice. However the perspectives of family, whānau and health professionals continue to show significant variation regarding the communication given and received around declining oral intake towards the end of life.

ObjectivesThe Liverpool Care Pathway (LCP) is a quality instrument for the dying patient. This study evaluates barriers and facilitators to its implementation in the Netherlands from the perspective of key stakeholders, to inform future implementation processes.MethodsAn interview study was conducted among 28 stakeholders involved in implementation of the LCP in the Netherlands, followed by a consecutive focus group with 8 interviewees to discuss and validate the findings of the interview study. Interviews were conducted by telephone and the notes taken during the interviews and focus group were transcribed into non-verbatim transcripts. Data collected during the interviews and focus group were evaluated using thematic analysis.ResultsAccording to the stakeholders, a context analysis prior to implementation was useful to find the appropriate orientation to adequately motivate healthcare professionals as well as management. The main contributing factors were the quality of the LCP (including its evidence-based character and completeness), and that it fitted the needs of healthcare professionals. During the implementation phase, a multidisciplinary project team, competent support and continuous monitoring were identified as important facilitators. Furthermore, for successful implementation, a facilitator working in liaison with others was helpful. To guarantee sustainability of the use of the LCP, it was important to disentangle tasks from the project leader and formally integrate these into the quality systems of the organisation.ConclusionsThe Dutch experience with large-scale implementation of the LCP has identified important barriers and facilitators to the implementation of a quality instrument within palliative care. To successfully implement such a promising instrument, liaison with others is important. The sense of being part of a process of improvement is valuable, while consolidation of this idea contributes to successful implementation.

BACKGROUND: Although guidelines advise titration of palliative sedation at the end of life, in practice the depth of sedation can range from mild to deep. We investigated physicians’ considerations about the depth of continuous sedation. METHODS: We performed a qualitative study in which 54 physicians underwent semistructured interviewing about the last patient for whom they had been responsible for providing continuous palliative sedation. We also asked about their practices and general attitudes toward sedation. RESULTS: We found two approaches toward the depth of continuous sedation: starting with mild sedation and only increasing the depth if necessary, and deep sedation right from the start. Physicians described similar determinants for both approaches, including titration of sedatives to the relief of refractory symptoms, patient preferences, wishes of relatives, expert advice and esthetic consequences of the sedation. However, physicians who preferred starting with mild sedation emphasized being guided by the patient’s condition and response, and physicians who preferred starting with deep sedation emphasized ensuring that relief of suffering would be maintained. Physicians who preferred each approach also expressed different perspectives about whether patient communication was important and whether waking up after sedation is started was problematic. INTERPRETATION: Physicians who choose either mild or deep sedation appear to be guided by the same objective of delivering sedation in proportion to the relief of refractory symptoms, as well as other needs of patients and their families. This suggests that proportionality should be seen as a multidimensional notion that can result in different approaches toward the depth of sedation.

Artificial hydration in end-of-life care is an important and emotive topic that frequently raises concerns from patients, relatives and healthcare professionals (HCPs). The aim of this review was to give an overview of currently available evidence around opinions and attitudes towards artificial hydration at the end of life.

During the dying phase, patients often receive interventions that are not aimed at promoting their comfort. We investigated how recognition of the dying phase affects the use of interventions by comparing patients for whom the dying phase had been recognized with patients for whom it had not been recognized. We included 489 of 613 patients (80%) who died either in a hospital, nursing home, or primary care setting between November 2003 and February 2006. After the death of patients, nurses filled in questionnaires, and patient records were searched for information about therapeutic and diagnostic interventions applied during the dying phase. Caregivers had recognized the dying phase of 380 patients (78%). The number of patients who had received diagnostic interventions during the last three days of life was significantly lower when the dying phase had been recognized (39% vs. 57%) (p=0.00). Therapeutic interventions were used in similar frequencies in both groups. We conclude that recognition of the dying phase reduces the number of undesirable diagnostic interventions.

Bisphosphonate pharmacokinetics may affect individual responses. Skeletal retention of pamidronate infused monthly to patients with bone metastases was highly variable (12‐98%) and did not diminish with time, showing the capacity of the skeleton to retain large amounts of bisphosphonate. Relationships between skeletal retention of pamidronate and rate of bone resorption are complex and depend on previous treatment and the total amount of retained bisphosphonate.

Bisphosphonate pharmacokinetics may affect individual responses. Skeletal retention of pamidronate infused monthly to patients with bone metastases was highly variable (12‐98%) and did not diminish with time, showing the capacity of the skeleton to retain large amounts of bisphosphonate. Relationships between skeletal retention of pamidronate and rate of bone resorption are complex and depend on previous treatment and the total amount of retained bisphosphonate.Introduction: Bisphosphonates (BPs) given intravenously every 3–4 weeks are effective in the management of metastatic bone disease from breast cancer, but responses among patients vary, and it is not known whether current dose and dose intervals are appropriate for an individual patient. An influence of pharmacokinetics of BPs on antiresorptive action may contribute to this variation in response. To test this hypothesis, we determined the skeletal retention of intravenous pamidronate and its association to the rate of bone resorption in patients with bone metastases from breast cancer.Materials and Methods: In a cross‐sectional study, 24‐h urinary excretion of pamidronate and the biochemical marker of bone resorption N‐terminal telopeptide of type 1 collagen and serum alkaline phosphatase were measured in 40 patients with bone metastases from breast cancer at the beginning, after 3–6 months, and after 1 year of treatment with intravenous pamidronate 90 mg every 3–4 weeks.Results and Conclusions: Skeletal retention (dose − amount excreted into urine) 2 days after infusion varied between 12% and 98% (mean, 62%) of the administered dose, but there were no differences in retention between patients receiving pamidronate for the first time or after 3–6 months or after 1 year of treatment. Retention of pamidronate was related to the prevalent rate of bone turnover in previously untreated patients, whereas no such relationship was found in previously treated patients. Rate of bone resorption after treatment seemed to be related to the amount of pamidronate retained. During 1 year of treatment, retention of pamidronate remained constant, indicating no saturation of skeletal binding sites with treatment. The variability in retention among individual patients can be attributed to the number of available binding sites. This is related, however, to bone turnover only before the start of treatment. The apparent relationships between skeletal retention and antiresorptive effect could have implications for the design of optimal therapeutic regimens with BPs in patients with bone metastases from breast cancer.

The non-ionic surfactants Cremophor EL (CrEL) and Tween 80,both used as formulation vehicles of many (anticancer) agentsincluding paclitaxel and docetaxel, are not physiologicalinert compounds. We describe their biological properties,especially the toxic side effects, and their pharmacologicalproperties, such as modulation of P-glycoprotein activity. Indetail, we discuss their influence on the disposition of thesolubilized drugs, with focus on CrEL and paclitaxel, and ofconcomitantly administered drugs. The ability of thesurfactants to form micelles in aqueous solution as well asbiological fluids (e.g. plasma) appears to be of greatimportance with respect to the pharmacokinetic behavior of theformulated drugs. Due to drug entrapment in the micelles,plasma concentrations and clearance of free drug changesignificant leading to alteration in pharmacodynamiccharacteristics. We conclude with some perspectives related tofurther investigation and development of alternative methodsof administration.

This review describes the clinical relevance of the two drugtransporters P-glycoprotein (Pgp) and multidrugresistance-associated protein (MRP) and the in vitrophenomenon which is referred to as multidrug resistance (MDR).The attempts to try to block these resistance mechanisms aresummarized with specific attention for the intentionallydesigned ``second generation'' MDR-convertors. Potentialexplanations of the limited clinical success rate are given andrecommendations for the design of future studies provided.

In 47 children with malignancy, zinc status, growth, and performance during standard treatment were compared with those in controls. At diagnosis, growth was retarded and hair zinc values were high, 2.4±0.7 μmol/g, as in chronic deficiency. During induction therapy, serum declined to 10.4±2.3 μmol/L and urinary excretion increased to 5.3±2.8 μmol/mol creatinine, as in acute exacerbation of deficiency. Control CSF values in children in remission, 0.04±0.01 μmol/L, were lower than reference values in adults. No difference in mean CSF zinc was observed during therapy, or in those with acute lymphoblastic leukemia (1) at high risk, (2) with central nervous system involvement, (3) with low performance, or (4) resistant to therapy. In six children unexplained values, up to 0.28 μmol/L during induction, were measured. No correlations between the various zinc parameters were found.

OBJECTIVE: To examine health professionals’ experiences of and attitudes towards the provision of chemotherapy to patients with end stage cancer. Design Purposive, qualitative design based on in-depth interviews. Setting Oncology departments at university hospitals and general hospitals in the Netherlands. Participants 14 physicians and 13 nurses who cared for patients with metastatic cancer. RESULTS: Physicians and nurses reported trying to inform patients fully about their poor prognosis and treatment options. They would carefully consider the (side) effects of chemotherapy and sometimes doubted whether further treatment would contribute to patients’ quality of life. Both groups considered the patients’ wellbeing to be important, and physicians seemed inclined to try to preserve this by offering further chemotherapy, often followed by the patient. Nurses were more often inclined to express their doubts about further treatment, preferring to allow patients to make the best use of the time that is left. When confronted with a treatment dilemma and a patient’s wish for treatment, physicians preferred to make compromises, such as by "trying out one dose." Discussing death or dying with patients while at the same time administering chemotherapy was considered contradictory as this could diminish the patients’ hope. CONCLUSIONS: The trend to greater use of chemotherapy at the end of life could be explained by patients’ and physicians’ mutually reinforcing attitudes of "not giving up" and by physicians’ broad interpretation of patients’ quality of life, in which taking away patients’ hope by withholding treatment is considered harmful. To rebalance the ratio of quantity of life to quality of life, input from other health professionals, notably nurses, may be necessary.