Drug Dosing at the End of Life: a Pharmacometric Approach

Drug dosing at the end of life is currently predominantly done according to the clinical response. This however takes time which is unwanted in the case of palliative care because of the limited life expectancy. As the palliative population is very heterogeneous in terms of co-morbidities and disease state, we performed several studies to see if we could identify patient or disease char

Prevalence of palliative care needs in patients admitted to hospital with heart failure

Background: The syndrome of heart failure is common, and is associated with high morbidity and reduced life expectancy. Patients can experience high symptom burden, low mood, and impaired quality of life. Repeated, and often prolonged, hospitalisations due to exacerbations of heart failure and other co-morbidities are common. Over the last 25 years, the evidence base for the treatment of heart failure has increased, with an associated improvement in prognosis. However, many patients with heart failure still have a poor prognosis. International guidelines for the treatment of heart failure now suggest referral to palliative care services, particularly in patients thought to have a poor prognosis and impaired quality of life. Despite these recommendations, few patients with this condition have access to specialist palliative care services in the United Kingdom. However, not every patient with heart failure will have palliative care needs, therefore the extent of the problem of unmet palliative care needs in patients with heart failure is unknown. I systematically reviewed the published literature to identify studies describing the palliative care needs, including prevalence, of patients with heart failure. Although my search identified over 60 publications describing the palliative care needs of patients with heart failure, most of the studies were of highly selected cohorts, did not include descriptions of therapy, or descriptions of severity of heart failure such as ejection fraction, natriuretic peptides, prognostic scores or clinical outcomes. Most studies used a cross-sectional approach to describe the potential palliative care needs, and therefore, were unlikely to appreciate the variable clinical course of patient with heart failure. Although the studies identified were informative, a definitive description of the prevalence of palliative care needs in a well described, contemporary cohort of patients with heart failure is lacking. My systematic review also identified a number of preliminary randomised controlled clinical trials, assessing the effect of early palliative care in patients with heart failure. However, these studies included small numbers of participants, and only had qualitative endpoints such as change in quality of life measures without assessment of clinical outcomes such as death or hospitalisation. Again, although these preliminary trials are informative, a definitive evidence base comparing palliative care to standard care in heart failure is not available. Aims: The primary aim of this study was to inform the design of a randomised controlled clinical trial of palliative care in patients with heart failure. The first step in this process was to define the clinical problem and identify a suitable target population by describing the prevalence of patients with heart failure who have palliative care needs. I then aimed to describe whether these patients could be identified from data collected during an index hospital admission. The final aim of my study was to identify useful outcome measures which could be used in a randomised controlled clinical of palliative care in heart failure. Methods: This was a prospective, longitudinal study of the prevalence of possible palliative care needs, defined using quantifiable patient reported outcome measures. An unselected cohort of patients admitted to hospital with a primary diagnosis of heart failure were recruited and extensively characterised. The World Health Organisation definition of palliative care was used to identify patients with heart failure who had palliative care needs. I made objective assessments of quality of life (using the Kansas City Cardiomyopathy and Short Form 12 questionnaires), mood disturbance (using the Hospital Anxiety and Depression Scale), symptom burden (using the Edmonton Symptom Assessment Scale), and caregiver strain (using the Zarit Burden Interview questionnaire). These assessments were made at baseline and repeated every four months for the duration of the study. Patients were identified as having palliative care needs if they had persistently severe impairment of any patient reported outcome measure without improvement, or severe impairment of any patient reported outcome measure followed by death. End-of-life care was assessed using the Views Of Informal Caregivers Evaluation of Services questionnaire, and by comparing preferred place of end of life care to actual place of death. Multivariate logistic regression analysis was used to determine if baseline prognostic markers, physician completed assessments, or patient reported outcome measures could identify patients with palliative care needs. Results: Between January 9th 2013 and December 1st 2014, 313 near consecutive patients with heart failure were enrolled in the study. Of these, 272 (86.9%) completed patient reported outcome measures at baseline and agreed to attend study visits. Patients were elderly, with a median [interquartile range] age of 76 [70-82] years, and 47% of participants were female. 56% of patients did not have a previous diagnosis of heart failure. Most participants had heart failure with reduced ejection fraction (67.3%) compared to heart failure with preserved ejection fraction (32.7%). Use of disease modifying pharmacotherapy was high, especially in participants with heart failure with reduced ejection fraction. Participants suffered from a number of physical and psychological symptoms, as recorded using patient reported outcome measures. The most common physical symptoms were shortness of breath and fatigue, followed by drowsiness and lack of appetite. Although less frequent, pain and nausea were also common. Participants reported higher scores for depression and anxiety compared to studies using similar mood assessments in the general population. Quality of life was impaired in most participants at baseline, with 77.9% of participants being classified as having moderate or severe impairment as assessed by the Kansas City Cardiomyopathy questionnaire. At baseline, 114 (41.9%) participants scored severe in at least one patient reported outcome measure. Of these, 95 (83%) participants scored severe on the Kansas City Cardiomyopathy Questionnaire. Participants were invited to attend study visits, or have home study visits, every four months for the duration of the study. The minimum number of study visits offered was two for the last participant enrolled. A total of 691 study visits were performed. 37% of these assessments were home visits. Participants were also followed up passively using record linkage to report number and cause of hospitalisations, and cause and location of any deaths. Participants were followed up for a minimum of one year. During follow-up, 217 (79.8%) participants were re-admitted to hospital. The median number of admissions was 3. Most hospitalisations were due to non-cardiovascular causes. During passive follow-up until December 1st 2015, there were 103 (37.8%) deaths. Most (60.2%) deaths were due to cardiovascular causes. 73 (26.8%) participants met my criteria for having palliative care needs. These patients had worse summary scores at baseline for all patient reported outcome measures. Patients who met my definition of palliative care needs spent fewer days alive and out of hospital than the group who did not meet the definition of palliative care needs. The median [IQR] days alive out of hospital in the group meeting the definition of palliative care needs was 394 [172-586], compared to 638 [420-809] in the group not meeting the definition of palliative care needs (p<0.001). After adjusting days alive out of hospital for quality of life, patients in the palliative care needs group had fewer days of good health as a percentage of total follow-up, median 12 [3-22] % of potential follow-up, compared to 47 [25-68] % in those not meeting my definition of palliative care needs (p<0.001). Most participants expressed a wish to spend the end of their life at home, but despite this, most died in hospital. 17 caregivers completed the Views Of Informal Caregivers Evaluation of Services questionnaire. Overall care in the last few months of life was assessed as fair or poor by 35.3%. Of the 272 participants who participated in the whole study, 33 (12.1%) had access to specialist palliative care services. Of the 73 participants who met the definition of PC needs, 19 (26.0%) accessed specialist PC services. 6 (2.2%) participants used hospice care during the duration of the study. Using multivariate logistic regression analysis, a low Kansas City Cardiomyopathy Questionnaire summary score and a low Australia Modified Karnofsky Performance Scale (a physician completed assessment) score, were predictive of patients with palliative care needs. Conventional prognostic markers, such as natriuretic peptides or ejection fraction, were not predictive of patients with palliative care needs. Physicians, using their clinical judgement, were only modestly accurate at predicting patients with heart failure who had or would go on to develop palliative care needs. Physicians were better at predicting prognosis than need for palliative care. Conclusions: Palliative care needs were common in patients with heart failure admitted to hospital with heart failure, with 26.8% of participants meeting my definition of palliative care needs. This study has shown there is an unmet need for palliative care in many patients with heart failure, with a marked discrepancy between the patients who met the definition of palliative care needs and those who accessed specialist palliative care services. I have also shown that patients with heart failure who go on to develop palliative care needs can be identified during a hospitalisation, using a combination of a patient reported outcome measure and a physician completed assessment. Patients who met my definition of palliative care needs had 40% fewer days alive and out of hospital than those who did not. The quality of days alive out of hospital was much worse. This thesis also provides important pilot data describing the quality of life adjusted days alive out of hospital of a “real life”, unselected, and therefore, generalisable cohort of patients with heart failure. I hope that these data, including the detailed description of a suitable target population, will inform the design of a randomised controlled clinical trial assessing the benefit of early palliative care in patients with heart failure

Clinical Nutrition: Recent Advances and Remaining Challenges

Nutrition, often along with physical activity, is by now acknowledged as a cornerstone in the prevention and even more so the treatment of many diseases. Indeed, food and nutritional intake nowadays are often thought to be the main source of wellbeing sometimes over- but also underestimating the impact of nutritional intake, dietary pattern and food-derived natural compounds in their impact on human health. In this Special Issue entitled `Clinical Nutrition: Recent Advances and Remaining Challenges´ a broad overview and summary on recent findings in various fields of clinical nutrition with special focus on chronic and degenerative diseases like metabolic diseases, cancers, neurodegenerative diseases, inflammatory bowel diseases, sarcopenia but also malnutrition in elderly, infants and children is provided. Nutrition, often along with physical activity, is by now acknowledged as a cornerstone in the prevention and even more so the treatment of many diseases. Indeed, food and nutritional intake nowadays are often thought to be the main source of wellbeing sometimes over- but also underestimating the impact of nutritional intake, dietary pattern and food-derived natural compounds in their impact on human health. In this Special Issue entitled `Clinical Nutrition: Recent Advances and Remaining Challenges´ a broad overview and summary on recent findings in various fields of clinical nutrition with special focus on chronic and degenerative diseases like metabolic diseases, cancers, neurodegenerative diseases, inflammatory bowel diseases, sarcopenia but also malnutrition in elderly, infants and children is provided