Lia van Zuylen

Role of formulation vehicles in taxane pharmacology

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.

The effect of the Liverpool Care Pathway for the dying: a multi-centre study:

We studied the effect of the Liverpool Care Pathway (LCP) on the documentation of care, symptom burden and communication in three health care settings. Between November 2003 and February 2005 (baseline period), the care was provided as usual. Between February 2005 and February 2006 (intervention period), the LCP was used for all patients for whom the dying phase had started. After death of the patient, a nurse and a relative filled in a questionnaire. In the baseline period, 219 nurses and 130 relatives filled in a questionnaire for 220 deceased patients. In the intervention period, 253 nurses and 139 relatives filled in a questionnaire for 255 deceased patients. The LCP was used for 197 of them. In the intervention period, the documentation of care was significantly more comprehensive compared with the baseline period, whereas the average total symptom burden was significantly lower in the intervention period. LCP use contributes to the quality of documentation and symptom control.

Palliative Sedation in a Specialized Unit for Acute Palliative Care in a Cancer Hospital: Comparing Patients Dying With and Without Palliative Sedation

Palliative sedation is undergoing extensive debate. The aims of this study were to describe the practice of palliative sedation at a specialized acute palliative care unit and to study whether patients who received palliative sedation differed from patients who did not. We performed a systematic retrospective analysis of the medical and nursing records of all 157 cancer patients who died at the acute palliative care unit between 2001 and 2005. Palliative sedation, defined as continuous deep sedation prior to death, was used for 43% of all deceased patients. In 87% of the sedated patients, it was started in the last two days before death. Sedated and nonsedated patients did not differ in survival after admission (eight days vs. seven days, P=0.12). Sedated patients were younger (55 years vs. 59 years, P=0.04) and more often had malignancies of the digestive tract (P<0.01). In both groups, common symptoms at admission were pain (79% vs. 87%, P=0.23), constipation, (40% vs. 48%, P=0.46), and dyspnea (32% vs. 29%, P=0.77). On the day that palliative sedation was started, sedated patients more often suffered from dyspnea and delirium than nonsedated patients at a comparable day before death. The most important indications for palliative sedation were terminal restlessness (60%) and dyspnea (46%). We conclude that at the studied acute palliative care unit, patients who ultimately received palliative sedation did not have symptoms different than nonsedated patients at admission, but on the day at which the sedation was started, they suffered more often from delirium and dyspnea.

Understanding provision of chemotherapy to patients with end stage cancer: qualitative interview study

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.

Inter-relationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients

Cremophor EL (CrEL) is a castor oil surfactant used as a vehicle for formulation of a variety of poorly water-soluble agents, including paclitaxel. Recently, we found that CrEL can influence the in vitro blood distribution of paclitaxel by reducing the free drug fraction, thereby altering drug accumulation in erythrocytes. The purpose of this study was to investigate the clinical pharmacokinetics of CrEL, and to examine inter-relationships of paclitaxel disposition, infusion duration and CrEL kinetics. The CrEL plasma clearance, studied in 17 patients for a total of 28 courses, was time dependent and increased significantly with prolongation of the infusion duration from 1 to 3 to 24 h (p<0.03). An indirect response model, applied based on use of a Hill function for CrEL concentration-dependent alteration of in vivo blood distribution of paclitaxel, was used to fit experimental data of the 3 h infusion (r2=0.733; p=0.00001). Simulations for 1 and 24 h infusions using predicted parameters and CrEL kinetic data revealed that both short and prolonged administration schedules induce a low relative net change in paclitaxel blood distribution. Our pharmacokinetic/pharmacodynamic model demonstrates that CrEL causes disproportional accumulation of paclitaxel in plasma in a 3 h schedule, but is unlikely to affect drug pharmacokinetics in this manner with alternative infusion durations.

Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases

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.

Considerations of physicians about the depth of palliative sedation at the end of life

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.

Prevalence, Impact, and Treatment of Death Rattle: A Systematic Review

CONTEXT Death rattle, or respiratory tract secretion in the dying patient, is a common and potentially distressing symptom in dying patients. Health care professionals often struggle with this symptom because of the uncertainty about management. OBJECTIVES To give an overview of the current evidence on the prevalence of death rattle in dying patients, its impact on patients, relatives, and professional caregivers, and the effectiveness of interventions. METHODS We systematically searched the databases PubMed, Embase, CINAHL, PsychINFO, and Web of Science. English-language articles containing original data on the prevalence or impact of death rattle or on the effects of interventions were included. RESULTS We identified 39 articles, of which 29 reported on the prevalence of death rattle, eight on its impact, and 11 on the effectiveness of interventions. There is a wide variation in reported prevalence rates (12%-92%; weighted mean, 35%). Death rattle leads to distress in both relatives and professional caregivers, but its impact on patients is unclear. Different medication regimens have been studied, that is, scopolamine, glycopyrronium, hyoscine butylbromide, atropine, and/or octreotide. Only one study used a placebo group. There is no evidence that the use of any antimuscarinic drug is superior to no treatment. CONCLUSION Death rattle is a rather common symptom in dying patients, but it is doubtful if patients suffer from this symptom. Current literature does not support the standard use of antimuscarinic drugs in the treatment of death rattle.

Awareness of dying: it needs words.

PurposeThe purpose of this research is to study to what extent dying patients are aware of the imminence of death, whether such awareness is associated with patient characteristics, symptoms and acceptance of dying, and whether medical records and nurses’ and family caregivers’ views on patients’ awareness of dying agree.MethodsNurses and family caregivers of 475 deceased patients from three different care settings in the southwest Netherlands were requested to fill out questionnaires. The two groups were asked whether a patient had been aware of the imminence of death. Also, medical records were screened for statements indicating that the patient had been informed of the imminence of death.ResultsNurses completed questionnaires about 472 patients, family caregivers about 280 patients (response 59%). According to the medical records, 51% of patients had been aware of the imminence of death; according to nurses, 58%; according to family caregivers, 62%. Patients who, according to their family caregiver, had been aware of the imminence of death were significantly more often in peace with dying and felt more often that life had been worth living. Inter-rater agreement on patients’ awareness of dying was fair (Cohen’s kappa = 0.23–0.31).ConclusionsBeing aware of dying is associated with acceptance of dying, which supports the idea that open communication in the dying phase can contribute to the quality of the dying process. However, views on whether or not patients are aware of the imminence of death diverge between different caregivers. This suggests that communication in the dying phase of patients is open for improvement.

End-of-Life Decision Making for Cancer Patients in Different Clinical Settings and the Impact of the LCP

Differences in the general focus of care among hospitals, nursing homes, and homes may affect the adequacy of end-of-life decision making for the dying. We studied end-of-life decision-making practices for cancer patients who died in each of these settings and assessed the impact of the Liverpool Care Pathway for the Dying Patient (LCP), a template for care in the dying phase. Physicians and relatives of 311 deceased cancer patients completed questionnaires. The LCP was introduced halfway through the study period. During the last three months of life, patients who died in hospital received anticancer therapy and medication to relieve symptoms more often than those in both other settings. During the last three days of life, patients who died in the hospital or nursing home received more medication than those who died at home. The LCP reduced the extent to which physicians used medication that might have hastened death. Relatives of patients who died in the hospital tended to be least positive about the patients and their own participation in the decision making. We conclude that cancer patients who die in the hospital are more intensively treated during the last phase of life than those who die elsewhere. The LCP has an impact on the use of potentially life-shortening medication during the dying phase. Communication about medical decision making tends to be better in the nursing home and at home.