How to conduct research in palliative care? A perspective from Italy.

BACKGROUND: In western countries, the increasing life expectancy and the growing number of individuals with advanced chronic conditions have resulted in a greater demand for palliative care. Specifically, Italy has witnessed substantial growth in the palliative care field, marked by the establishment of Palliative Care Networks and an academic fellowship program in 2022. To further enhance this field, it is crucial to conduct high-quality scientific research that produces results applicable in clinical practice. AIM: This article explores challenges and potential solutions in conducting effective palliative care research, considering sample definition, research settings, outcomes, and ethical concerns. While focusing on the Italian context, the presented research framework can be applied to other contexts and regions. RESULTS: Palliative care research is complex and challenging due to its holistic approach, which encompasses various vital dimensions of patients and their families, including physical, emotional, and social needs. The Italian and worldwide experience provides insights into managing these challenges and enhancing the methodological rigor of studies and the practical application of research findings. CONCLUSIONS: This article emphasizes the importance of developing protocols tailored to palliative care's unique characteristics, and the necessity of dedicated funding for palliative care research, calling for increased support and recognition. The article advocates for improvement of the quality and relevance of palliative care studies, promoting better patient outcomes and enhanced caregiving.

[Overview and symptom management in heart failure patients eligible for palliative care]. / Inquadramento e gestione dei sintomi nel cardiopatico candidato a cure palliative.

Burden symptom in advanced heart failure highly affects quality of life of both patients and caregivers, leading to severe functional limitation and social isolation. Symptoms in the advanced phases of the disease are numerous and often underestimated and undertreated. This negatively affects not only quality of life, but also increases hospitalizations, reduces therapeutic adherence, impairs cardiac function and leads to reduced survival. When symptom control cannot be achieved only with specific cardiologic therapy, optimal care should shift to a combination of life-prolonging and symptom-relief approach, possibly to be initiated as soon as advanced phases are detected. Optimal treatment of severe and invalidating symptoms requires a multi-modal and multi-dimensional approach, as pharmacological therapy represents only a part of a global evaluation that should include spiritual and psycho-social factors, potentially influencing symptom perception. Assessment therefore should rely on multi-modal and multi-dimensional patient-centered score models, such as the Edmonton Symptom Assessment System (ESAS), the Kansas City Cardiomyopathy Questionnaire (KCCQ), or the Integrated Palliative care Outcome Scale (IPOS).Pain, dyspnea, depression, fatigue and less frequent but distressing symptoms, including gastrointestinal disorders (nausea, vomiting, fecal impaction, hiccups), cough, itching, skin xerosis and restless legs syndrome, will be analyzed, and evidence of best palliative practice will be discussed.

[Selection criteria to palliative care implementation in advanced heart failure]. / Criteri di selezione del malato con scompenso cardiaco da avviare a cure palliative.

Early palliative care (PC) integration in advanced and end-stage heart failure has shown to improve quality of life and spiritual well-being and to reduce physical symptoms. Barriers to implementation exist: perception that PC is opposite to "life-prolonging" therapies or is involved only in cancer disease and in end of life, prognostic difficulties in advanced heart failure, comorbidities, discrepancy between patient-reported symptom burden and objective measures of disease severity. This is why it is necessary to focus on patient and caregivers "needs" instead of exclusively numerical-objective measures, in order to emphasize clinical but also psychological, assistential and spiritual elements contributing to quality of life. The most appropriate instruments are "patient-reported outcome measures" (PROMs) or, better, "patient-centered outcome measures" (PCOMs), such as the Needs Assessment Tool: Progressive Disease-Heart Failure (NAT: PD-HF), Integrated Palliative Outcome Scale (IPOS), NECPAL and Supportive and Palliative Care Indicators Tool (SPICT). Finally, it is important to recognize triggers to initiate a PC approach (important changes in disease trajectory, difficult or refractory symptoms, frequent defibrillator shocks or transplant/mechanical support prevision, functional capacity decline, severe comorbidities, communication needs also for advanced care planning).

[Palliative care and heart failure: some remarks about cost-effectiveness and clinical results]. / Cure palliative e scompenso cardiaco: considerazioni su costo-efficacia e risultati clinici.

Early palliative care (PC) clearly demonstrated its efficacy in patients with heart failure (HF), reducing symptom burden, mainly pain and depression, improving quality of life, and reducing the access to the health care system. However, there are not conclusive data on economic cost reduction. The reasons are related to the few patients involved in the studies dedicated to this topic, to the different clinical settings, different modalities of provision and funding of PC, and different timing of PC implementation. PC was not shown to reduce mortality nor hospital readmissions in randomized trials.The unanswered questions will be clarified only in larger studies, defining specific clinical settings, goals to achieve and standardizing the provision and funding modalities in the different countries.

[Palliative care in the cardiac setting: a consensus document of the Italian Society of Cardiology/Italian Society of Palliative Care (SIC/SICP)]. / Documento di consenso sulle cure palliative in ambito cardiologico a cura del Gruppo di Lavoro congiunto della Società Italiana di Cardiologia (SIC) e della Società Italiana di Cure Palliative (SICP).

Palliative care is recognized as an approach that improves quality of life of patients and families facing life-threatening illnesses. This is achieved through prevention, early identification, assessment and treatment of symptoms and other psycho-social, spiritual and economic issues. Palliative care is not dependent on prognosis and can be delivered as "simultaneous care", together with disease-modifying treatments and adequate symptom relief. Palliative care relies on coordination across settings of care and offers open communication to patients and caregivers. Recently, there is increasing interest in the potential role of palliative care in refractory, advanced heart failure treated with optimal, maximized therapy.Heart failure is a chronic progressive syndrome characterized by periods of stability interrupted by acute exacerbations, usually leading to reduced functional status. It accounts for approximately one-third of deaths in industrialized countries and is a common cause of hospitalization. Fifty percent of patients with advanced heart failure die within 1 year of diagnosis and 50% of the remainder within 5 years. The trajectory of heart failure is often unpredictable and approximately 30% to 50% of patients die suddenly. Patients with heart failure suffer from numerous symptoms, often resistant to conventional treatments, frequently under-recognized and under-treated. Symptom assessment and control improve quality of life in patients with advanced heart failure; this can be managed at best by collaboration between specialistic teams.Although heart failure is a life-shortening condition, therapeutic and technological advances (such as left ventricular assist devices, coronary revascularization, percutaneous valve implantation, and implantable cardioverter defibrillators) can help healthcare professionals in the management of patients with advanced heart failure, improving global condition and reducing the risk of sudden death. On the other hand, it has to be acknowledged that management of cardiovascular implanted electronic devices towards end of life requires awareness of legal, ethical, religious principles regarding potential withdrawal of life-sustaining therapies.Adequate communication with patients regarding adverse events, end of life, benefits vs burdens of therapies and interventions, treatment preferences, and decision-making should be an issue in early stages of disease. The process of advanced care planning should be clearly documented and regularly reviewed.Barriers to the provision of palliative care in heart failure include clinical issues (disease trajectory), prognostic uncertainty, failure in identification of patients who need palliative care and timing of referral to specialist services, but also misconceptions of patients, families and sanitary staff regarding the role of palliative care, organization problems, and finally educational and time issues.This document focuses on the need of further, coordinated research and work-out on: (i) identification of heart failure patients eligible for palliative care, in terms of clinical and social-psychological issues, (ii) identification of trigger events and timing of referral; (iii) identification of adequate performance indicators/scales for measurement, assessment and follow-up of symptoms and quality of life in end-stage heart failure, including patient-reported outcome measures; (iv) treatment, care and organization strategies and models for advanced/end-stage heart failure ("care management"); and (v) implementation of knowledge and education of healthcare professionals in the fields of communication, ethics, and advanced care planning in heart failure.

Nonresponsiveness and Susceptibility of Opioid Side Effects Related to Cancer Patients' Clinical Characteristics: A Post-Hoc Analysis.

BACKGROUND: The response to opioids is not always positive in cancer patients. A considerable proportion of patients do not respond (nonresponders [NRs]) or experience severe toxicity. The aim of this analysis was to assess the role of demographic characteristics, pain features, comorbidities, and ongoing therapy on the lack of efficacy and on the occurrence of severe adverse drug reactions (ADRs). METHODS: This is a post-hoc analysis of a randomized controlled trial that involved 520 patients and aimed to evaluate the efficacy and safety of 4 strong opioids. Patients who presented with unchanged or worsened pain compared to the first visit were considered to be NRs. As for toxicity, severe ADRs with an incidence of greater than 10% were evaluated. Univariate and multivariate logistic models were used. RESULTS: 498 patients were analyzed. Liver metastases and breakthrough pain (BTP) were found to increase the risk for nonresponse. Conversely, a high basal pain intensity significantly decreased the same risk. Constipation risk was worsened by previous weak opioid therapy but decreased with aging and with the use of transdermal opioids. Risk for drowsiness was aggravated by bone metastases and concomitant treatment with anticoagulant, antidiabetic, and central nervous system drugs. Risk for confusion increased with antidiabetics, antibiotics, and previous weak opioid therapy but decreased when fentanyl was used. Occurrence of nausea increased in patients with a high rating on the Karnofsky Performance Status Index. Risk for xerostomia was higher in women and in patients treated with antidiabetic or long-term opioids. CONCLUSIONS: Several clinical variables are correlated with opioid response in cancer patients. In particular, the presence of BTP is associated with nonresponse. Additionally, patients who receive polypharmacological therapy are more likely to experience opioid adverse events.

Whey protein ingestion enhances postprandial anabolism during short-term bed rest in young men.

We tested the relative ability of rapidly digested whey and slowly digested casein to stimulate net whole-body protein synthesis during prolonged physical inactivity. We studied 8 young male volunteers after they consumed isonitrogenous casein or whey mixed meals on d 12 or d 14 of experimental bed rest. Rates of phenylalanine hydroxylation were measured by primed-constant oral administration of L[2-(2)H(2)]tyrosine and L[ring-(2)H(5)]phenylalanine for 3 h in the postabsorptive state and 6 h after an isonitrogenous bolus meal containing sucrose (0.27 g/kg) and casein or whey (0.40 g/kg). Net protein synthesis in the fed state was calculated during the first 6 h postmeal as the difference between phenylalanine hydroxylation and phenylalanine content in the ingested casein or whey. In the fed state, the integrated changes in phenylalanine hydroxylation were lower (P < 0.05) after whey (-2 +/- 8 micromol x kg(-1) x 6 h(-1)) than after casein ingestion (34 +/- 7 micromol x kg(-1) x 6 h(-1)). During bed rest, net postprandial protein synthesis was greater (P < 0.05) after whey (96 +/- 8 micromol phenylalanine x kg(-1) x 6 h(-1)) than after casein ingestion (82 +/- 7 micromol phenylalanine x kg(-1) x 6 h(-1)). The rapidly digested whey protein was more efficient than the slowly digested casein in increasing postprandial net protein synthesis during short-term bed rest.

Glutathione metabolism in sepsis.

Sepsis is characterized by severe redox imbalance. Glutathione plays a major role in cellular defenses against oxidative and nitrosative stress. There is limited information on the response of glutathione synthesis in human sepsis. This review proposes a critical analysis of available data on potential factors affecting glutathione synthesis in sepsis. Glutathione is synthesized from its constituent amino acids--glutamate, cysteine, and glycine. Cysteine availability and the activity of the enzyme glutamate cysteine ligase are rate-limiting for glutathione synthesis. Glutathione synthetic capacity is increased in liver and other tissues during the acute phase of experimental sepsis. Potential mechanisms for glutamate cysteine ligase activation in sepsis involve a decreased ratio of reduced/oxidized glutathione as well as the effects of reactive oxygen species, nitric oxide species, proinflammatory cytokines, heat shock proteins, and physical inactivity. Glutathione synthesis can be impaired by cysteine depletion, protein-energy malnutrition, hyperglycemia, glucocorticoid at pharmacologic doses, and decreased secretion of anterior pituitary hormones (growth hormones, thyrotropin, gonadotropins), as often observed in prolonged critical illness.

Calorie restriction accelerates the catabolism of lean body mass during 2 wk of bed rest.

BACKGROUND: Muscle inactivity and low energy intake commonly occur in persons with acute or chronic disease, in astronauts during space flight, and during aging. OBJECTIVE: We used a crossover design to investigate the effects of the interactions of inactivity and calorie restriction on whole-body composition and protein kinetic regulation in 9 healthy volunteers. DESIGN: Lean body mass (LBM) was measured by using dual-energy X-ray absorptionmetry before and at the end of 14-d periods of bed rest (B) and controlled ambulation (A) in patients receiving eucaloric (E) or hypocaloric (H) (approximately 80% of total energy expenditure) diets. Whole-body leucine kinetics were determined at the end of the 4 study periods by using a standard stable-isotope technique in the postabsorptive state and during a 3-h infusion of a 0.13 g x kg LBM(-1) x h(-1) amino acid mixture. RESULTS: In the postabsorptive state, we found a significant (P = 0.04) bed rest x hypocaloric diet interaction for the rate of leucine oxidation, an index of net protein catabolism (A+E: 0.23 +/- 0.01; B+E: 25 +/- 0.01; A+H: 0.23 +/- 0.01; B+H: 0.28 +/- 0.01 micromol x min(-1) x kg LBM(-1)). Bed rest significantly (P < 0.01) decreased amino acid-mediated stimulation of nonoxidative leucine disappearance, an index of protein synthesis (A+E: 35 +/- 2%; B+E: 30 +/- 2%; A+H: 41 +/- 3%; B+H: 32 +/- 2%). B+H decreased LBM by 1.10 +/- 0.1 kg, which is significantly (P < 0.01) greater than the decrease seen with A+E, A+H, or B+E. CONCLUSION: Calorie restriction enhanced the catabolic response to inactivity by combining greater protein catabolism in the postabsorptive state with an impaired postprandial anabolic utilization of free amino acids.

Response of muscle protein and glutamine kinetics to branched-chain-enriched amino acids in intensive care patients after radical cancer surgery.

OBJECTIVE: Patients with cancer are characterized by decreased muscle protein synthesis and glutamine availability that contribute to an impaired immune response. These abnormalities worsen after surgical stress. We tested the hypothesis that pharmacologic doses of branched-chain amino acids would improve the early metabolic response after major cancer surgery. METHODS: By using a crossover experimental design, we compared the metabolic effects of isonitrogenous solutions of balanced and branched-chain-enriched amino acid mixtures infused at the rate of 82 mg x h(-1) x kg(-1) for 3 h in patients with colorectal or cervical cancer on the first and second days after radical surgery combined with intraoperative radiation therapy. The ratios of leucine to total amino acid (grams) in the two mixtures were 0.09 and 0.22, respectively. Muscle protein and glutamine kinetics were determined by using stable isotope of amino acids and the leg arteriovenous balance technique. Glucose and insulin were continuously infused throughout the 2-d study to maintain near euglycemia. RESULTS: Rates of muscle protein synthesis and degradation were not significantly affected by the balanced amino acid infusion. In contrast, the isonitrogenous, branched-chain-enriched amino acid mixture accelerated muscle protein turnover by stimulating (P

Muscle glutamine depletion in the intensive care unit.

Glutamine is primarily synthesized in skeletal muscle and enables transfer of nitrogen to splanchnic tissues, kidneys and immune system. Discrepancy between increasing rates of glutamine utilization at whole body level and relative impairment of de novo synthesis in skeletal muscle leads to systemic glutamine deficiency and characterizes critical illness. Glutamine depletion at whole body level may contribute to gut, liver and immune system disfunctions, whereas its intramuscular deficiency may directly contribute to lean body mass loss. Severe intramuscular glutamine depletion also develops because of outward transport system upregulation, which is not counteracted by increased de novo synthesis. The negative impact of systemic glutamine depletion on critically ill patients is suggested both by the association between a lower plasma glutamine concentration and poor outcome and by a clear clinical benefit after glutamine supplementation. Enteral glutamine administration preferentially increases glutamine disposal in splanchnic tissues, whereas parenteral supplementation provides glutamine to the whole organism. Nonetheless, systemic administration was ineffective in preventing muscle depletion, due to a relative inability of skeletal muscle to seize glutamine from the bloodstream. Intramuscular glutamine depletion could be potentially counteracted by promoting de novo glutamine synthesis with pharmacological or nutritional interventions.

Mechanisms of malnutrition in uremia.

Loss of lean body mass is common in chronic renal failure and may adversely affect morbidity and mortality of patients. The pathogenesis of protein wasting in chronic renal failure is multifactorial and is reviewed by the authors. When protein kinetics are determined in patients with uncomplicated uremic on conservative treatment by isotopically labeled amino acids, the results indicate that the rates of both protein synthesis and degradation are decreased both at whole body and skeletal muscle levels. On the other hand, if a complication is superimposed (ie, acidosis or infection), protein turnover accelerates, primarily because of proteolysis increase. Therapeutical implications are analyzed in this article. Recently, a cytokine-induced chronic inflammatory response has been proposed to explain the progressive protein loss often observed in these patients even in the absence of complications. Cytokine concentrations often have been found to be increased in both dialyzed and undialyzed chronically uremic patients. Tumor necrosis factor (TNF)-alpha clearance is reduced in uremia because this cytokine is catabolized and excreted mainly by the kidneys. In addition, we found that gene expression for TNF-alpha in circulating blood cells is enhanced in chronically uremic patients, suggesting that an activation of the systemic inflammatory response may contribute to the metabolic, vascular, and immune complications of this disease.

Mechanisms of altered protein turnover in chronic diseases: a review of human kinetic studies.

PURPOSE OF REVIEW: Changes in hormone secretion, tissue perfusion, oxygen availability, energy-protein intake, free amino acid pattern, hydration state, acid-base balance as well as activation of the systemic inflammatory response may affect protein synthesis and degradation. The overall purpose of this review is to describe how these factors may interact to change protein turnover in the different directions seen in kinetic studies in humans. RECENT FINDINGS: Evidence indicates that, in vivo, changes of protein synthesis and degradation are strictly related. When protein synthesis is primarily suppressed, protein degradation is found to be unchanged or even slightly decreased. When protein degradation is primarily accelerated, the rate of synthesis is unchanged or even increased. Chronic disease states can, therefore, be characterized either by decreased or accelerated protein turnover. Apparent discrepancies among various studies in chronic uraemia, liver cirrhosis, chronic obstructive pulmonary disease and cancer may stem from the fact that the pathogenesis of protein metabolism abnormalities is multifactorial. When the effects of inflammatory mediators and stress hormones start overwhelming factors that tend to decrease protein synthesis and turnover (decreased protein-energy intake, physical activity, tissue oxygen delivery, leucine levels, etc.), the rate of protein degradation and turnover may increase. SUMMARY: Low-protein turnover conditions are usually associated with the adequate sparing of body proteins, whereas in high-protein turnover conditions protein loss may proceed at a faster rate. Nonetheless, impaired recovery from acute complications and the reduced renewal of damaged and toxic proteins are potential undesired consequences of low-protein turnover.