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Overview of managing common non-pain symptoms in palliative care

Overview of managing common non-pain symptoms in palliative care
Authors:
Eduardo Bruera, MD
Rony Dev, DO
Section Editor:
Thomas J Smith, MD, FACP, FASCO, FAAHPM
Deputy Editor:
Jane Givens, MD
Literature review current through: Apr 2021. | This topic last updated: Feb 23, 2021.

INTRODUCTION — Most patients in the terminal phase of a serious and/or life-threatening illness, such as cancer, develop potentially devastating physical, psychosocial, and existential distress in the weeks to months before death [1]. Patients admitted to tertiary palliative care units are likely to present with more frequent and severe symptoms compared with those admitted to community hospices or acute care hospital beds, although the frequency of symptoms is high in all groups (table 1).

Effective treatment will successfully alleviate, and may even eliminate, the majority of symptoms (pain, dyspnea, nausea/vomiting, fatigue, etc) that arise in terminally ill patients.

Palliative care is an interdisciplinary medical specialty that focuses on preventing and relieving unnecessary suffering by supporting the best possible quality of life for patients and their loved ones facing serious and/or life-threatening illness. The primary tenets of palliative care are symptom management; establishing goals of care that are in keeping with the patient’s values and preferences; consistent and sustained communication between the patient and all those involved in their care; psychosocial, spiritual, and practical support both to patients and their families or caregivers; and coordination across sites of care. Palliative care aims to relieve suffering in all stages of disease and is not limited to end-of-life care. Within an integrated model of medical care, palliative care is provided at the same time as curative or life-prolonging treatments. (See "Benefits, services, and models of subspecialty palliative care".)

Referral to palliative care at an earlier stage of an advanced, serious, or life-threatening illness may reduce the symptom burden of patients and prepare family caregivers for the last stages of life. In a seminal study of patients with metastatic non-small-cell lung cancer, early palliative care consultation led to modest improvements in quality of life and mood, longer median survival, and less intravenous chemotherapy administered within 60 days before death [2]. (See "Benefits, services, and models of subspecialty palliative care", section on 'Definitions'.)

This topic will provide a brief overview of the management of common non-pain symptoms in adult palliative care patients [1]. Other palliative care issues are discussed elsewhere:

(See "Overview of comprehensive patient assessment in palliative care".)

(See "Approach to symptom assessment in palliative care".)

(See "Cancer pain management with opioids: Optimizing analgesia".)

(See "Legal aspects in palliative and end-of-life care in the United States".)

(See "Ethical issues in palliative care".)

(See "Physician-assisted dying".)

(See "Psychosocial issues in advanced illness".)

(See "Hospice: Philosophy of care and appropriate utilization in the United States".)

(See "Pediatric palliative care".)

(See "Communication in the ICU: Holding a family meeting".)

(See "Palliative care: Issues in the intensive care unit in adults".)

(See "Withholding and withdrawing ventilatory support in adults in the intensive care unit".)

(See "Ethics in the intensive care unit: Responding to requests for potentially inappropriate therapies in adults".)

Much of the information presented in the following sections is derived from studies of patients with cancer, since this group has been studied more than any other group with advanced life-threatening illness. However, the principles are equally applicable to patients with other advanced life-limiting diseases, such as heart failure, dementia, chronic obstructive pulmonary disease (COPD), end-stage kidney disease (ESKD), and neuromuscular diseases such as amyotrophic lateral sclerosis (ALS). Symptom control issues in the terminal phase of illness that are unique to patients with heart failure and ESKD are discussed separately. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Symptom management' and "Kidney palliative care: Principles, benefits, and core components", section on 'Terminal symptom management'.)

CHALLENGES FOR SYMPTOM MANAGEMENT AT THE END OF LIFE — Symptom management of terminally ill patients can be complicated by several factors [3]:

Older age (two-thirds are age 65 years or older)

Malnutrition, low serum albumin

Decreased renal function

Impaired cognition

Lower seizure threshold (metastatic brain involvement, use of opioids)

Long-term opioid therapy

Multiple-drug therapy

Frequent autonomic nervous system impairment

Some of these characteristics, such as malnutrition, low serum albumin, and decreased renal function, may seriously affect the pharmacokinetics of drugs used for symptom control. In addition, terminally ill patients are often frail and tolerate lower doses of drugs compared with other medically or psychiatrically ill patients.

The high frequency of autonomic nervous system failure increases the risk of some side effects from opioids, tricyclic antidepressants, and phenothiazines, including constipation, dry mouth, nausea, urinary retention, and postural hypotension [4]. The presence of impaired cognition and use of opioids and other psychoactive drugs are all risk factors for delirium or sedation, both of which limit the ability of patients to function and interact with family or friends.

Symptom assessment — Terminally ill patients often present with multiple symptoms and are frequently severely fatigued, distressed, and demoralized. Thus, symptom assessment should be simplified. A number of tools have been developed that allow for repeated assessment and graphically display the intensity of different symptoms [5]. These tools utilize descriptions of intensity using numbers, words, colors, fingers of the hand, or circles of gradually increasing size, and appear to be reliable. As an example, the Edmonton Symptom Assessment Scale (ESAS) or revised ESAS are visual analogue scales that have been validated and utilized in multiple palliative care settings (table 2). (See "Approach to symptom assessment in palliative care", section on 'Assessment and rating instruments for symptoms'.)

Periodic symptom reassessment is valuable for identifying or modifying treatment goals, monitoring the response to specific symptomatic interventions, and communicating between members of the health care team.

Some symptoms have prognostic significance. Poor performance status (table 3), a measure of a patient’s functional status, has been associated with a short survival in cancer patients. Other symptoms, such as weight loss, dyspnea, fatigue, and pain, have been also associated with poor prognosis in patients with advanced cancer [6,7]. In addition, certain clinical signs, such as pulselessness of the radial artery, respiration with mandibular movement, decreased urine output, Cheyne-Stokes breathing, and the “death rattle,” strongly indicate imminent death within three days [8]. These signs, when present, provide health care providers with information that should be thoughtfully communicated to family members or other caretakers in order to facilitate advanced care planning. (See "Approach to symptom assessment in palliative care", section on 'Performance status, symptoms, and prognosis' and "Palliative care: The last hours and days of life", section on 'Recognizing the dying patient'.)

Importance of communication — Open and regular communication with both the patient and their loved ones is essential to achieve adequate symptom palliation. They may have severe emotional, spiritual, and sometimes financial distress. Information regarding findings, medications, and expected changes may need to be repeated several times by health care professionals. The use of graphs, question-prompt lists [9], written material, or audiocassettes of consults can increase recall and satisfaction with information [10]. Written materials such as brochures may improve communication between health care providers and patients as well as their families or caregivers [11,12]. Audiotapes and web-based videoconferencing technology can also be used to inform persons who cannot be present for face-to-face discussions.

Breaking bad news can be difficult for clinicians [13], who may have the perception that disclosing prognostic information will result in depression, loss of hope, and even decreased survival, which is unfounded. Patients who have had end-of-life discussions do not have higher rates of depression [14], loss of hope [15], or decreased survival [16]. Open, honest, and empathetic communication is critical to providing palliative care, and guidelines have been developed to assist clinicians with this important task [17-19]. Benefits of more open and honest communication between cancer patients and health care providers include improved patient understanding and a more realistic estimate of survival, allowing patients to choose end-of-life care consistent with their own wishes and preferences [20].

Conferences with family or loved ones can facilitate communication between patients and their caregivers. Results of prospective cohort trials in the intensive care unit setting have shown that such end-of-life conferences are associated with improvement in family/loved ones’ satisfaction, reduction in length of stay, and increased access to palliative care, without an increase in mortality [21,22]. Similar studies in other settings are lacking. (See "Communication in the ICU: Holding a family meeting".)

Health care providers need to take into consideration the information needs of both patients and their caregivers before engaging in discussions of end-of-life issues. Systematic interviews reveal that caregivers have distinct information needs concerning prognosis and other end-of-life issues, which often differ from those of patients [23]. In addition, preferences for information may change over time. As an example, one study found that patients with terminal cancer asked fewer questions about their diagnosis and, in general, were less involved with decision-making as their disease progressed [24].

Even if they have completed an advance directive, patients with a serious, life-threatening illness often face challenging treatment choices, and high-quality discussions about what is important to them promote good decision-making and patient-centered care. Understanding the patient’s values, preferences, and care goals in the context of a serious illness allows the clinician to align the care provided with what is most important to the patient. Discussing goals of care is a unique skill that should be separated conceptually from talking about prognosis or delivering bad news. While discussions about goals of care may involve some of the same principles as other difficult communication tasks, these discussions demand a different framework. (See "Discussing goals of care" and "Advance care planning and advance directives".)

Research regarding interventions to improve the quality of communication with patients with serious illness is ongoing. Initial studies report that communication quality improvements result in increased documentation of serious-illness conversations [25]. However, a cluster randomized clinical trial of a communication intervention (the Serious Illness Care Program) failed to improve goal-concordant care or peacefulness at the end of life, although it did reduce patient depression and anxiety [26].

FATIGUE — Fatigue (asthenia, weakness) is the most common symptom in palliative care; it is also one of the most underdiagnosed and undertreated. Untreated or undertreated fatigue significantly affects the quality of life of patients receiving palliative care, and appropriate assessment and management of fatigue is essential. (See "Overview of fatigue, weakness, and asthenia in palliative care".)

Fatigue is typically a multidimensional symptom, often with multiple contributing causes. The major contributors to fatigue in patients with advanced cancer are outlined in the table (table 4).

Anemia is a particularly important contributor in patients undergoing cancer treatment. However, the importance of anemia is diminished towards the end of life for cancer patients and for others with nonmalignant serious and/or life-threatening illnesses, in whom other contributing factors, such as psychological symptoms, including anxiety and depression, as well as pain, cachexia, side effects of medications, physical inactivity, and infection, may play a greater role. (See "Overview of fatigue, weakness, and asthenia in palliative care", section on 'Causes and pathophysiology' and "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)

The assessment of fatigue in palliative care patients can be complex given its subjective and multidimensional nature. As such, there is a trend towards multidimensional assessment (ie, asking about different aspects of fatigue, such as muscular weakness or tiredness associated with a sleep disturbance) rather than asking a single question, “Are you tired?” (See "Approach to symptom assessment in palliative care", section on 'Fatigue'.)

A comprehensive history and physical examination is indicated to identify potentially reversible etiologies. Review of all medications, including prescriptions, over-the-counter medications, and alternative/complementary therapies, is particularly important to identify side effects and potential drug-drug interactions that may be contributing to fatigue. Simply altering the dose or dosing interval may substantially improve fatigue. Management of fatigue includes aggressive treatment of reversible causes, if any are identified (table 5). If a specific cause cannot be identified, symptomatic management is appropriate. All patients should be counseled as to coping strategies that conserve energy (table 6 and table 7).

In the setting of palliative care, there are limited data to support one pharmacologic approach to fatigue over any other [27]. For patients in the terminal phase of illness who have a high symptom burden that includes fatigue, a two-week trial of a glucocorticoid (eg, prednisone 20 to 40 mg or dexamethasone 4 to 8 mg every morning) is reasonable [28]. The role of psychostimulants is not well defined, particularly for patients with serious and/or life-threatening illnesses other than cancer. However, a trial of methylphenidate (eg, starting with 5 mg every morning and increasing, as needed, to 5 mg in the morning and at noon, 10 mg in the morning and 5 mg at noon, then 10 mg in the morning and at noon) or modafinil is reasonable for fatigued patients when opioid-related sedation is a contributing factor. Overall, studies have found that psychostimulants provide no significant improvement in cancer-related fatigue compared with placebo. Ginseng may have the potential to improve cancer-related fatigue, although a trial did not demonstrate benefit over placebo [29]. (See "Overview of fatigue, weakness, and asthenia in palliative care", section on 'Pharmacologic approaches' and "Cancer-related fatigue: Treatment", section on 'Interventions'.)

Nonpharmacologic approaches that may be helpful include moderate exercise, yoga, and cognitive-behavioral therapy. (See "Cancer-related fatigue: Treatment", section on 'Nonpharmacologic interventions' and "Overview of fatigue, weakness, and asthenia in palliative care", section on 'Nonpharmacologic approaches'.)

PAIN — Pain is the most distressing and feared symptom by patients and their loved ones. Pain affects approximately 80 percent of cancer patients before death. Fortunately, good or excellent pain control can be achieved in most cases. (See "Cancer pain management: General principles and risk management for patients receiving opioids".)

In many cases, the constellation of symptoms and signs can suggest a specific cancer pain syndrome, such as metastatic bone involvement or a brachial plexopathy. The identification of such a syndrome may help to elucidate the etiology of the pain, direct the diagnostic evaluation, clarify the prognosis for the pain or the disease itself, and guide therapeutic intervention. If no etiology for the underlying pain syndrome is evident, clinicians should consider other patient-related factors, such as delirium, somatization, and depression [30]. The assessment and management of the different cancer pain syndromes are discussed separately. (See "Assessment of cancer pain" and "Overview of cancer pain syndromes".)

Opioids are the mainstay of therapy for moderate or severe pain. Prior to prescribing opioids, screening for chemical coping or risk for opioid use disorder with tools such as the CAGE alcoholism screening questionnaire, the Screener and Opioid Assessment for Patients with Pain (SOAPP), or the Opioid Risk Tool (ORT) should be conducted in order for clinicians to minimize risk of non-medical opioid use (NMOU) resulting in unnecessary opioid toxicity and to identify patients who may need appropriate psychosocial support [30]. Unfortunately, screening tools alone may be inadequate to identify NMOU. At least one study has documented the effectiveness of random urine drug testing [31]. Specific issues related to risk assessment prior to prescribing opioids and to assessment and management of pain in the last weeks of life are discussed in detail separately. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment and management for patients receiving opioids'.)

GASTROINTESTINAL SYMPTOMS

Nausea with or without vomiting — Nausea has many causes in patients with a serious and/or life-threatening illness. The most common causes of nausea and vomiting in palliative care patients are outlined in the table (table 8); most patients have two or more contributing factors. (See "Assessment and management of nausea and vomiting in palliative care", section on 'Pathophysiology and etiology'.)

Cancer patients — An effort should be made to identify and correct reversible underlying causes. This may include correction of metabolic abnormalities, aggressive bowel care, opioid rotation, and treatment of brain metastases. The general approach to nausea and emesis that is related to antineoplastic therapy (including breakthrough nausea and vomiting) and nausea related to opioid use is discussed separately. (See "Assessment and management of nausea and vomiting in palliative care", section on 'Advanced cancer not receiving antitumor therapy' and "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults" and "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment" and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Nausea and vomiting'.)

Early satiety and vomiting of food eaten several hours earlier suggests gastroparesis. Dietary modification and pharmacologic management (eg, with prokinetics such as metoclopramide) are discussed separately. (See "Assessment and management of nausea and vomiting in palliative care", section on 'Gastroduodenal dysmotility' and "Malignancy-associated gastroparesis: Pathophysiology and management" and "Treatment of gastroparesis".)

For cancer patients with an inoperable malignant bowel obstruction who are not candidates for a colonic stent (in whom a prokinetic agent would be contraindicated), dexamethasone and haloperidol are the drugs of choice to control nausea. In addition, drugs capable of decreasing the amount of gastrointestinal secretions and gut motility (eg, subcutaneous octreotide alone or in combination with anticholinergic agents such as glycopyrrolate) may help to control nausea and vomiting. (See "Assessment and management of nausea and vomiting in palliative care", section on 'Gastrointestinal obstruction' and "Management of small bowel obstruction in adults", section on 'Malignant obstruction'.)

If a potentially reversible cause cannot be identified and bowel obstruction is ruled out, symptomatic treatment with a prokinetic agent such as metoclopramide (10 mg every four hours around the clock to a maximum of 120 mg/day) is often helpful due to its combination of central antiemetic and peripheral gastric emptying effects. Slow-release metoclopramide is more effective than the rapid-release formulation in the control of chronic nausea. It is available in Europe and Latin America but not in the United States. Alternatives to metoclopramide for the control of nausea include haloperidol (oral, intravenous [IV] 0.5 to 2 mg every six to eight hours as needed) and olanzapine (oral, 5 to 10 mg/day). (See "Assessment and management of nausea and vomiting in palliative care", section on 'No obvious cause'.)

Non-cancer conditions — Few data are available to guide the assessment and management of nausea and vomiting in palliative care patients with diseases other than cancer. This subject is discussed in detail elsewhere. (See "Assessment and management of nausea and vomiting in palliative care", section on 'Non-cancer conditions'.)

Constipation — Bowel movements vary in frequency between individuals, ranging from one every third day to three per day. The term constipation has varied meanings for different people. For some, it may mean that stools are too hard or too small, or that defecation is too difficult or infrequent. The first three complaints are difficult to quantify in clinical practice; the last can be measured and compared with the general population. (See "Etiology and evaluation of chronic constipation in adults", section on 'Definition of constipation'.)

The prevalence of constipation among palliative care populations varies widely from 18 to 90 percent [32-35]. A main source of this variance is how constipation is defined by patients and health care providers. The influence of specific definition on prevalence of constipation can be illustrated by a cross-sectional survey of 485 patients in 38 palliative care units in Sweden [35]. The prevalence of constipation ranged from 7 to 43 percent, depending on the definition used and how constipation was assessed. A strict frequency-based definition (≤3 stools per week) resulted in a prevalence of 7 percent, but when the definition included the patient’s perception of being constipated in the last two weeks, the prevalence rose to 43 percent.

In addition to differences in how constipation is defined both by patients and providers, other factors explaining this variance include the lack of common agreement regarding the definition, specific mix of diagnoses and stages of illness in individual reports, effect of medications such as opioids, and interference with identification because of multiple other symptoms, underreporting, and lack of adequate documentation in medical and nursing records.

Risk factors for constipation in patients with a serious or life-threatening illness include advanced disease, older age, decreased physical activity, low-fiber diet, depression, and cognitive impairment. Medications that can cause or exacerbate constipation include opioids, calcium channel blockers, diuretics, anticholinergic drugs, iron, serotonin antagonists, and chemotherapy (vinca alkaloids, thalidomide, vandetanib). There are also neural (eg, epidural spinal cord compression) and metabolic abnormalities (hypercalcemia and hypothyroidism) that may cause or contribute to constipation.

Assessment of the palliative care patient with constipation is addressed separately. (See "Approach to symptom assessment in palliative care", section on 'Constipation'.)

Treatment of constipation includes addressing potentially reversible nonpharmacologic factors (table 9), stopping nonessential constipating medications, and pharmacologic interventions (laxative therapy).

The choice of laxative therapy is empiric. A Cochrane review of laxatives for constipation in patients receiving palliative care concluded that there was no evidence on whether individual laxatives were more effective than others or caused fewer adverse effects [36].

Senna, a peristaltic stimulant, may be started initially and titrated (over-the-counter dosing range for sennosides 8.6 to 8.8 mg once daily [maximum 70 to 100 mg/day]) to soften daily bowel movements. Two studies [37,38] have failed to demonstrate additional benefit when adding docusate to senna for the treatment of constipation; however, in refractory cases, a short therapeutic trial of combined therapy may be indicated.

Other pharmacologic treatments (table 10) include bulk-forming laxatives (cellulose, psyllium, bran), osmotic laxatives (lactulose, sorbitol, polyethylene glycol, magnesium hydroxide, magnesium citrate), and surfactants (docusate). Stimulant laxatives other than senna (bisacodyl, castor oil) may be helpful short-term agents. Because stimulant laxatives cause intestinal contractions, their use can be limited by abdominal cramps and pain. This can sometimes be avoided by dividing the total dose into smaller, more frequent doses [39,40].

Enemas (eg, with soapsuds mineral oil, or milk and molasses) and/or rectal-based laxatives administered as suppositories may be indicated for distal fecal impaction or if a patient has not had bowel movement for three days or more. Digital stimulation and manual disimpaction may be necessary if fecal impaction is suspected. Due to discomfort associated with manual evacuations, these interventions should be considered a last resort and may require premedication with pain medications and/or anxiolytics [39].

Patients with refractory opioid-induced constipation may benefit from one of several opioid antagonists. These are discussed in detail elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Management of refractory opioid-induced constipation'.)

Xerostomia — Xerostomia, the sensation of a dry mouth, is a common symptom affecting patients with a life-limiting illness. A dry mouth can alter taste and make it difficult for patients to eat and swallow [41].

There are a number of causes for xerostomia, which include radiation therapy, chemotherapy, surgery (particularly for head and neck cancers), drugs (anticholinergics, antidepressants, opioids, anxiolytics, antihistamines, beta-blockers), dehydration, and oral infections [42]. (See "Approach to symptom assessment in palliative care", section on 'Dry mouth' and "Oral toxicity associated with chemotherapy", section on 'Xerostomia' and "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Salivary gland damage and xerostomia'.)

Frequent oral hygiene is the first step in treating xerostomia. Rinsing with cold water, sucking on ice chips, and chewing sugarless gum to increase salivation may provide comfort. For more severe cases, artificial saliva (solution, spray, or gel) may also be useful. Potentially beneficial approaches for patients who have radiation therapy-related xerostomia include acupuncture and oral pilocarpine. (See "Complementary and alternative therapies for cancer", section on 'Pain control and xerostomia' and "Management of late complications of head and neck cancer and its treatment", section on 'Stimulation of existing salivary flow'.)

Dysphagia — Difficulty with swallowing is a common symptom in patients who are terminally ill with an advanced, serious and/or life-threatening illness, especially head and neck cancer, esophageal cancer, and diseases that compromise neurologic function, such as amyotrophic lateral sclerosis (ALS). Dysphagia may also be due to a stricture following radiation therapy for an upper aerodigestive tract cancer. (See "Swallowing disorders and aspiration in palliative care: Definition, consequences, pathophysiology, and etiology" and "Oropharyngeal dysphagia: Etiology and pathogenesis" and "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Weight loss and malnutrition' and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Upper motor neuron symptoms' and "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Clinical manifestations'.)

Patients with dysphagia are at risk for aspiration. A bedside swallowing evaluation may be indicated if patients are noted to cough after swallowing. If abnormal, a barium swallowing study can assist with identifying aspiration. (See "Swallowing disorders and aspiration in palliative care: Assessment and strategies for management", section on 'Assessment'.)

Initial management of dysphagia includes modification of food and fluid consistency. Potentially reversible causes should be sought and treated. Patients treated for head and neck cancer may benefit from swallowing rehabilitation. Radiation therapy may be an option for esophageal obstruction that is caused by a locally advanced esophageal cancer or an extrinsically compressing mediastinal mass. Endoscopic methods of palliation may also be considered (eg, dilation of a stricture, placement of an intraluminal self-expanding stent, or laser ablation in the case of esophageal obstruction). (See "Swallowing disorders and aspiration in palliative care: Assessment and strategies for management" and "Use of expandable stents in the esophagus" and "Endoscopic palliation of esophageal cancer".)

Nonoral feeding may be recommended as a temporary solution for severe dysphagia that is expected to improve (eg, patients with head and neck cancer undergoing chemoradiotherapy, acute neurologic dysphagia from a cerebrovascular accident), and it may restore nutrition and hydration for patients with dysphagia after an acute illness such as stroke. For some chronic neurologic disorders (eg, ALS), limited data suggest that percutaneous gastrostomy tube (PEG) placement is associated with prolonged survival, although the degree of benefit for those with late-onset disease is uncertain. On the other hand, the available evidence suggests that there is no survival benefit (and no protection from aspiration) for PEG tubes in patients with end-stage dementia. In such cases, the decision to pursue nonoral feeding must be carefully considered. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Head and neck cancer' and "Symptom-based management of amyotrophic lateral sclerosis", section on 'Dysphagia, weight loss, and nutrition' and "Care of patients with advanced dementia", section on 'Oral versus tube feeding' and "Swallowing disorders and aspiration in palliative care: Assessment and strategies for management", section on 'Artificial nutrition and hydration'.)

CACHEXIA-ANOREXIA — Cachexia, a hypercatabolic state defined as accelerated loss of skeletal muscle in the context of a chronic inflammatory response, can occur in the setting of cancer as well as in chronic infection, acquired immunodeficiency syndrome (AIDS), heart failure, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD). While loss of appetite (anorexia) with weight loss is common among cancer patients, the profound weight loss suffered by patients with cachexia cannot be entirely attributed to poor caloric intake. (See "Assessment and management of anorexia and cachexia in palliative care".)

In some cases, cancer treatment (eg, androgen-deprivation therapy for advanced prostate cancer, sorafenib) may also contribute to loss of lean body mass. The clinical features and pathogenesis of cancer-associated anorexia-cachexia syndrome are discussed in detail separately. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)

Dietary intake patterns in the terminally ill include decreased frequency of eating, reduction in the variety of foods, and unusually high proportions of liquids [43]. Loss of appetite and change in eating patterns are often distressing, particularly to family members or other caretakers. A study of bereaved family members noted the following four domains of concern: (1) family members feeling that they forced the patient to eat to avoid death; (2) family members feeling that they made great efforts to help patients eat; (3) the lack of oral intake resulting in conflict between the patient and family; and (4) insufficient information regarding nutritional intake for cancer patients with cachexia [44].

Patients and their families or caretakers should be reassured that eating extra calories does not reverse the underlying process in patients with advanced disease, and that loss of interest in food is a natural occurrence as the illness progresses. The social benefits of eating with other loved ones at the dining table as well as the pleasure of tasting food should be emphasized over the nutritional benefits. Dysgeusia may be addressed by reducing red meat intake in favor of more dairy products, marinating meats before cooking and seasoning well to disguise bitter taste, serving foods at room temperature rather than hot, trying tart foods, and encouraging fluids with meals. Strong cooking smells should be avoided at mealtimes.

After potentially reversible causes of anorexia are ruled out (eg, constipation, nausea, mouth discomfort, electrolyte disturbances, depression), symptomatic treatment of cachexia is appropriate. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Assessment'.)

Patients with anorexia should be given permission to eat less, with small, frequent feedings rather than two or three large meals. Appetite stimulants may be beneficial, although the preponderance of evidence is in patients with cancer-associated cachexia-anorexia syndrome. Unfortunately, there is a lack of strong evidence for orexigenic agents for anorexia/cachexia in patients with other types of advanced illnesses, including heart failure, cystic fibrosis, advanced neurologic diseases including dementia, and AIDS. Furthermore, the primary benefits associated with these drugs are increased appetite and modest weight gain, not improved survival or quality of life.

Nevertheless, the following treatments may be beneficial:

Glucocorticoids can be administered orally and parenterally, and they are capable of improving appetite, nausea, and energy for brief periods of time. Dexamethasone (4 mg/day) or prednisone (20 mg) are often recommended when short-term treatment is being considered. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Glucocorticoids'.)

Megestrol acetate improves appetite and may have some effect on fatigue but not on nutritional status or quality of life. Megestrol acetate poses a significant risk of developing venous thrombosis, adrenal insufficiency, and possibly severe androgen deficiency in male patients [45]. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Megestrol acetate'.)

Cannabinoids such as dronabinol significantly improve appetite in patients with HIV/AIDS who have anorexia-cachexia; however, they have not shown activity against cancer-associated anorexia-cachexia. (See "Management of cancer anorexia/cachexia", section on 'Cannabis and cannabinoids'.)

A number of other pharmacologic interventions have shown some promise, including carnitine supplements, mirtazapine, and olanzapine; however, evidence of benefit from randomized controlled trials is lacking, and none can be recommended. Combination therapy (ie, carnitine supplements plus celecoxib) may be an effective treatment for anorexia-cachexia syndrome, but more research is needed. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Treatments needing further study' and "Management of cancer anorexia/cachexia", section on 'Insufficient evidence to recommend for or against'.)

Artificial nutrition and hydration — The great majority of patients in the terminal phase of an advanced, serious, or life-threatening illness, such as cancer, experience reduced oral intake before death, either voluntarily or because they are unable to take in sufficient nutrients and fluids because of loss of appetite, nausea, vomiting, dysphagia, generalized weakness, gastrointestinal tract obstruction, or impaired cognition. Family members and caregivers often experience high levels of emotional distress when a terminally ill patient becomes unable to take fluids and nourishment orally, fearing that dehydration and malnutrition will contribute to suffering and hasten death.

While nutrient supplementation might appear ideal to control or reverse malnutrition, for the vast majority of terminally ill patients, there is no evidence that artificial nutrition prolongs life or improves functional status [46], and it is not indicated. However:

For highly selected patients (eg, high-grade bowel obstruction or malabsorption from advanced cancer) who might otherwise have a prognosis that is measured in months, home parenteral nutritional support may be considered after extensive deliberation among the health care staff, the patient, and family members or other caretakers [47,48]. After initiation, the use of parenteral nutrition needs periodic reevaluation; if the benefits are outweighed by excessive harms, it should be discontinued.

For other terminal diseases, such as dementia or neurodegenerative disease, in which the patients will not or cannot eat, intervention with a percutaneous endoscopic gastrostomy (PEG) tube may be considered in selected patients. Maintaining or improving a patient’s quality of life, even in the short term; reducing pain and suffering; and providing access for hydration or medication delivery may be reasonable goals of PEG tube placement, even in patients with ultimately terminal diseases.

These issues are all discussed in detail elsewhere. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Indications and benefits of nutritional support in cancer patients' and "Gastrostomy tubes: Uses, patient selection, and efficacy in adults" and "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'End of life and cancer' and "Stopping nutrition and hydration at the end of life", section on 'Use of artificial nutrition' and "Care of patients with advanced dementia".)

Hydration in end-of-life care — The possibility that dehydration may contribute to suffering and hasten death in patients at the end of life has generated strong debate, with arguments for and against parenteral fluid administration (table 11). (See "Stopping nutrition and hydration at the end of life".)

The practice of administering hydration near the end of life varies greatly in different settings of care. The vast majority of cancer patients who die in acute care hospitals receive hydration until death, while most patients who die in hospice or at home receive no fluids. This is at least partly related to reimbursement issues. Without a need for intravenous therapy, utilization rules from third-party insurers make it difficult to justify billing for inpatient treatment. On the other hand, the per diem hospice funding mechanism makes the administration of parenteral fluids difficult to finance. (See "Hospice: Philosophy of care and appropriate utilization in the United States", section on 'Structure'.)

Whether or not hydration improves symptoms or quality of life at the end of life is uncertain; only limited data are available. At least one randomized, controlled, double-blind study comparing parenteral hydration with normal saline at a dose of 1000 versus 100 mL/day (placebo) in 129 patients enrolled in hospice observed no significant differences in symptoms, quality of life, or survival at days 4 and 7 between both groups; on the other hand, dehydration may be a cause of potentially reversible delirium at the end of life [49,50].

Decisions regarding the use of hydration should be individualized, and the decision process needs to involve the patient, family, other caregivers, and other health care professionals, including a careful assessment of potential benefits and drawbacks. This subject is discussed in detail separately. (See "Stopping nutrition and hydration at the end of life", section on 'Use of artificial hydration'.)

INSOMNIA — Insomnia is the inability to initiate or maintain sleep, or experiencing nonrestorative and unrefreshing sleep despite attempts [51]. Sleep disturbance is a common and distressing symptom for terminally ill patients. Besides adversely affecting quality of life, insomnia can heighten the intensity and awareness of other symptoms, such as pain, anxiety, or delirium.

An Edmonton Symptom Assessment System (ESAS) score of ≥4 has good sensitivity for screening sleep disorder, which often coexists with other symptoms such as pain and depression [52].

Initial management includes an aggressive attempt to treat pain and other associated factors as well as limitation or timely dosing of stimulating medications, including steroids or psychostimulants. Nonpharmacologic interventions involve modifying the environment, encouraging healthy sleep-wake cycles, and minimizing disruptions. Pharmacologic interventions include melatonin or selective, melatonin receptor agonists, and sedating antidepressants including mirtazapine or trazodone. (See "Overview of insomnia in palliative care".)

DEPRESSION, SUICIDAL IDEATION, AND DEMORALIZATION — Depression is the most common mental health problem encountered in palliative medicine, yet it is widely misdiagnosed and undertreated. Failure to diagnose and treat major depression impairs the quality of life of dying patients and adds to their burden of suffering. Individuals who suffer from depression are also at increased risk for suicide. (See "Assessment and management of depression in palliative care", section on 'Prevalence of depression in palliative care'.)

Depressed mood, sadness, and anticipatory grief are all normal responses in patients facing death. However, feelings of pervasive hopelessness, helplessness, worthlessness, excess guilt, loss of interest, and suicidal ideation (even mild or passive) are among the best indicators of major depression in such patients, as are vegetative signs (sleep disorder, poor concentration, anorexia, and psychomotor retardation) not explained by the underlying medical condition (table 12).

A careful diagnostic interview is the gold standard method for assessing whether patients are clinically depressed. However, a simple single question (“Have you been depressed most of the time for the past two weeks?”) and other abbreviated screening methods such as those recommended by the National Comprehensive Cancer Network (NCCN) [53] appear to be effective in identifying those patients who require further assessment for depression. Anticipatory grief, a natural and expected reaction to having a life-limiting illness and loss, can and should be distinguished from major depression. (See "Approach to symptom assessment in palliative care", section on 'Sadness, grief, depression, and demoralization' and "Assessment and management of depression in palliative care", section on 'Assessment and diagnosis'.)

Major depression is a treatable condition, even in terminally ill patients. The first step in treating depression is to relieve uncontrolled symptoms, particularly pain. For patients with major depression, supportive psychotherapy should be initiated, and sometimes this is sufficient to treat the condition. However, most experts recommend an approach that combines supportive psychotherapy with education for the patient and their loved ones, as well as judicious use of antidepressant medication. In general, clinicians should have a low threshold for pharmacologic treatment, even if the diagnosis is in question, because treatments for depression have become easier to use and tend to have fewer side effects than older medications. (See "Assessment and management of depression in palliative care", section on 'Treatment' and "Management of psychiatric disorders in patients with cancer", section on 'Depression'.)

Demoralization is a psychiatric syndrome characterized by feelings of hopelessness and helplessness, and a loss of purpose and meaning in patients with a terminal illness; it may be distinct from clinical depression [54] and precipitated by existential distress [55]. (See "Assessment and management of depression in palliative care", section on 'Existential concerns and spirituality'.)

Among the factors that are consistently associated with demoralization are poorly controlled physical symptoms, inadequately treated depression and anxiety, reduced social functioning, unemployment, single status [54], and, possibly, age and sex [56]. Treatment of demoralization in patients receiving palliative care can include cognitive-behavioral therapy, dignity therapy, meaning-centered psychotherapy, and access to spiritual care, but more research is needed in this area [55]. (See "Assessment and management of depression in palliative care", section on 'Existential psychotherapy'.)

DELIRIUM — For many terminally ill patients with cancer, chronic obstructive pulmonary disease (COPD), end-stage kidney disease (ESKD), heart failure, and other serious, life-threatening diseases, global cerebral dysfunction without a reversible underlying etiology, manifested as delirium, is the final common complication that precedes death. Delirium is the most common neuropsychiatric complication seen in patients with advanced cancer nearing the end of life [57] and can result in distress for patients, family members, caretakers, and health care providers [58]. Delirium has also been associated with adverse outcomes in patients undergoing treatment for cancer [50,59]. (See "Diagnosis of delirium and confusional states" and "Palliative care: The last hours and days of life", section on 'Delirium' and "Clinical features and diagnosis of cognitive impairment and delirium in patients with cancer", section on 'Delirium'.)

A number of factors may contribute to the development of delirium in patients with advanced terminal illness, including (see "Approach to symptom assessment in palliative care", section on 'Delirium' and "Clinical features and diagnosis of cognitive impairment and delirium in patients with cancer", section on 'Delirium'):

Opioid-induced neurotoxicity (see "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding')

Brain tumor/metastases

Cancer treatments (chemotherapy, radiation therapy) (see "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy" and "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview")

Psychotropic drugs (tricyclic antidepressants, benzodiazepines), other drugs with anticholinergic properties [60], and glucocorticoids

Metabolic factors (hypercalcemia, hyponatremia), dehydration, or failure of a vital organ or system (eg, renal failure, hypotension) (see "Hypercalcemia of malignancy: Mechanisms" and "Clinical manifestations of hypercalcemia" and "Overview of the treatment of hyponatremia in adults" and "Diagnostic evaluation of adults with hyponatremia")

Paraneoplastic syndromes (see "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic and autoimmune encephalitis")

Sepsis or even simple infections such as cystitis

For older patients, who are often frail, other factors may also precipitate delirium, including complications of myocardial infarction, hip fracture, pulmonary embolism, pain, and even constipation.

Several tools are available for screening for delirium, including the Memorial Delirium Assessment Scale (MDAS) (form 1A-B) [61] and the Confusion Assessment Method (CAM) (table 13) [62]. (See "Approach to symptom assessment in palliative care", section on 'Delirium' and "Diagnosis of delirium and confusional states" and "Clinical features and diagnosis of cognitive impairment and delirium in patients with cancer", section on 'Delirium'.)

Treatment — Haloperidol is the drug of choice for the symptomatic management of medically ill patients presenting with delirium, especially when there is evidence of psychomotor agitation, delusions, or hallucinations. Low doses are usually effective for agitation, paranoia, and fear. Typically 0.5 to 1 mg haloperidol (orally, intravenous, intramuscular, or subcutaneous) is administered, with repeat doses every 45 to 60 minutes titrated against symptoms. Older patients may require lower doses in order to avoid side effects, including extrapyramidal symptoms.

However, haloperidol should be considered a palliative measure, while other strategies, such as a change in the type of opioid, hydration, or the management of metabolic or infectious complications, are introduced. Hyperactive symptoms improve within three to five days in most patients if the underlying etiology is corrected. If no response is observed within 24 to 48 hours of administering full doses of haloperidol, other more-sedating neuroleptics, such as olanzapine or chlorpromazine, are potential alternatives in patients with persistent signs and symptoms of delirium.

There is limited evidence from clinical trials regarding optimal drug therapy for treatment of mild to moderate delirium in terminally ill patients [63-67]:

One trial randomly assigned 30 patients with acquired immunodeficiency syndrome (AIDS) who became delirious in the hospital to haloperidol, lorazepam, or chlorpromazine [65]. Treatment with either haloperidol or chlorpromazine resulted in significant improvement in delirium compared with baseline. The mean daily haloperidol dose in the first 24 hours of treatment was 2.8 mg (range 0.8 to 6.3 mg), and for chlorpromazine it was 50 mg (range 10 to 70 mg). Maintenance doses on subsequent days were approximately half the initial day’s requirement. Importantly, lorazepam was ineffective in managing delirium.

Clinical benefits and harms from haloperidol in palliative care patients were addressed in a prospective consecutive cohort of 119 palliative care patients (105 with cancer) from 14 centers across four countries who had haloperidol commenced because of delirium [66]. Overall benefit was defined as a one-grade reduction in symptom severity using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale for delirium (table 14), while a harm was recorded if the criteria for any NCI CTCAE toxicity grade were greater than a baseline assessment up to day 10 for that individual participant and it was thought to be directly attributed to the use of haloperidol. Overall, the average haloperidol dose was 2.1 mg per 24 hours; 42 of the 106 patients still alive at 48 hours (35 percent) reported benefit at that time point. Harm was reported in 14 of 119 assessable patients up to and including day 10, the most frequent being somnolence (n = 11) and urinary retention (n = 6). Overall, one in three participants gained a net clinical benefit at 10 days.

Evidence supporting the use of second-generation antipsychotics includes a retrospective study that examined treatment with haloperidol (mean dose 6 mg), aripiprazole (18 mg), olanzapine (7 mg), and risperidone (1 mg) in patients with cancer and delirium. Each drug was studied in 21 patients, and the mean age in the four groups ranged for 64 to 70 years [67]. Resolution of delirium within four to seven days of the initial assessment was comparable for the four groups (haloperidol 76 percent of patients, aripiprazole 76 percent, olanzapine 62 percent, and risperidone 86 percent). However, extrapyramidal side effects occurred in more patients who received haloperidol (19 percent) than in those who received other drugs, and sedation occurred more often with olanzapine (29 percent).

The benefit and safety of neuroleptics for treatment of delirium in palliative care patients were called into question by the results of a double-blind, randomized trial in which 247 patients in inpatient hospice or a hospital palliative care service with a life-limiting illness (cancer in 88 percent), mild to moderately severe delirium, and a target symptom of delirium-associated distress (sum of Nursing Delirium Screening Scale [NuDESC] Behavioral, Communication, and Perceptual items of 1 or more) were randomly assigned to age-adjusted titrated doses of oral risperidone, haloperidol, or placebo solution every 12 hours for 72 hours [63]. All patients also received individualized management of delirium precipitants, nonpharmacologic supportive care measures (hydration, vision and hearing aids, presence of loved ones, and reorientation), and subcutaneous midazolam, as needed, for severe distress or safety. The NuDESC score was significantly worse in patients randomized to receive antipsychotic drugs, who overall reported to have greater delirium severity, significantly increased use of subcutaneous midazolam, more extrapyramidal effects, and worse short-term survival. An increase in mortality has also been observed in patients with distressing behavioral and psychological symptoms of dementia who were treated with neuroleptic drugs [68], prompting the US Food and Drug Administration (FDA) to issue a black box warning against the use of atypical antipsychotic drugs in this population. (See "Management of neuropsychiatric symptoms of dementia", section on 'Drugs to avoid'.)

In our view, this study supports systematic screening for delirium, reversing precipitating causes, and providing best supportive care for symptomatic distress associated with mild to moderate delirium. However, in our view, the results of the study do not justify abandoning neuroleptics to manage agitated delirious patients, but instead support the need for additional research. Limitations of the study include the low dose of antipsychotics, which would be relatively ineffective in controlling symptoms; use of the oral route of administration, which increases risk for extrapyramidal symptoms [69]; coadministration of subcutaneous midazolam, which was lower in the placebo arm and may precipitate more agitation and confound assessment of extrapyramidal symptom side effects; and inclusion of patients only with MDAS scores (13 to 15 at baseline) that were consistent with mild to moderate but not severe delirium. In addition, data were not provided as to the specific identifiable precipitants of delirium and whether this differed among the groups.

Additional information on the benefits and risks of neuroleptics to treat delirium in the last hours and days of life, and the benefit of adding lorazepam for patients with persistent agitated delirium despite haloperidol [70] are provided elsewhere. (See "Palliative care: The last hours and days of life", section on 'Delirium'.)

Patients who are in the last days to hours of life who fail to improve with medical management of delirium may benefit from aggressive parenteral sedation, including the use of subcutaneous or intravenous infusions of midazolam. This highly liposoluble benzodiazepine is very potent and has a short half-life, allowing for rapid titration. In general, midazolam should normally be considered a short-term measure for delirious patients while other causes of reversible delirium are investigated and treated. (See "Palliative care: The last hours and days of life", section on 'Palliative sedation for patients with refractory symptoms' and "Palliative sedation", section on 'Administration'.)

DYSPNEA AND OTHER RESPIRATORY SYMPTOMS — Dyspnea, defined as an uncomfortable awareness of breathing, is a common symptom in terminally ill cancer patients (table 1) [71]. Dyspnea is particularly common in patients who have primary lung cancer or intrathoracic metastatic disease; however, it is also a common symptom in terminally ill patients who have no evident cardiopulmonary pathology. From a pathophysiologic standpoint, the sensation of dyspnea may arise from increased ventilatory demand, impairment of the mechanical process of ventilation, or both. A physiologic classification of the causes of dyspnea is presented in the table (table 15). (See "Assessment and management of dyspnea in palliative care", section on 'Pathophysiology'.)

Many patients with dyspnea due to one of the identifiable causes improve dramatically with specific treatments, such as anticoagulation for pulmonary embolism, antibiotics for pneumonia, or red blood cell transfusion for anemia. In other cases, the goal of the treatment in terminally ill patients is to improve the subjective sensation as expressed by the patient, rather than alleviation of the underlying condition.

Breathing training, relaxation, modification in activity level, chest wall vibration, and the use of bathroom aids, portable oxygen, and wheelchairs are tools to improve performance and increase the autonomy of patients and their families or caretakers. Systemic opioids are the most effective pharmacologic agents and the treatment of choice for symptomatic control of dyspnea. In addition, hypoxemic patients may benefit from oxygen supplementation. The assessment and management of dyspnea in the palliative care setting is discussed in detail separately. (See "Assessment and management of dyspnea in palliative care".)

Management of cough, stridor, and hemoptysis in palliative care patients is addressed separately. (See "Palliative care: Overview of cough, stridor, and hemoptysis".)

LYMPHEDEMA — Chronic edema, palpable swelling that is produced by expansion of the interstitial fluid volume and lasts greater than three months, may have multiple underlying etiologies (table 16). Among patients who are terminally ill with a serious and/or life-threatening illness, the most common causes of chronic extremity edema are venous obstruction, hypoalbuminemia, decreased mobility, fluid retention, and medications including corticosteroids.

Lymphedema occurs when the lymphatic load exceeds the transport capacity of the lymphatic system, which causes filtered protein-rich fluid to accumulate in the interstitium [5]. Lymphedema is generally due to disruption of lymphatic flow, which may be secondary to injury, surgery, radiation therapy, infection, or cancer. As compared with generalized edematous states, the rate of capillary filtration is normal in patients with lymphedema. (See "Clinical features and diagnosis of peripheral lymphedema", section on 'Normal lymphatic system and lymphedema'.)

Chronic lymphedema affects both physical and psychological wellbeing as a result of interruption of normal daily activities. Cancer patients with lymphedema are more likely to experience greater disability, poorer quality of life, and greater psychological distress as compared with cancer patients without lymphedema [72]. It may cause patients to feel distress and discomfort, and reduce mobility as well as function [73,74].

Lymphedema cannot be cured, but it requires complex and individualized management. The management of lymphedema, including a discussion of management in palliative care populations, is discussed in detail separately. (See "Clinical staging and conservative management of peripheral lymphedema", section on 'Complete decongestive therapy'.)

Among patients with refractory lymphedema in the palliative care setting, there are few data to guide optimal management. Options include:

Manual lymphatic drainage [75]

Compression therapy [76,77]

Complete decongestive therapy [78-80]

Exercise

Closed-controlled subcutaneous drainage (lymphcentesis) for lower extremity lymphedema [81-85]

Simple elevation of the extremity and skin care

A systematic review concluded that all studies examining specific therapeutic interventions in the palliative setting were small and uncontrolled, and few included objective measures of outcome; all were rated in the category of “effectiveness not established” [86].

Diuretics such as furosemide are usually of little benefit in chronic lymphedema and may promote the development of volume depletion. They are not indicated.

LAST HOURS OF LIFE — Patients and their loved ones are often unprepared for the changes that typically occur during the last hours of life and the actual moment of death. Health care professionals should explain the expected changes in cognition and physical function before they occur in order to alleviate distress, prevent panic, and decrease the burden of bereavement (table 17). Decreased level of consciousness, Palliative Performance Scale (PPS) ≤20 percent, and dysphagia of liquids had a high frequency during the last three days of life but a low specificity (<90 percent) for death within three days. However, periods of apnea, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, pulselessness of radial artery, respiration with mandibular movement, and decreased urine output occurred less frequently during the last three days of life, but these signs have a high specificity (>95 percent) for death within three days [8]. These discussions are particularly useful for families or caretakers planning a home death or for those closely involved in institutional care. (See "Palliative care: The last hours and days of life", section on 'Preparing the family for physiologic changes in the dying process'.)

Frequent misconceptions by families or caretakers include:

The interpretation of purposeless movements, facial expressions, or other bodily movements as expressions of physical discomfort or emotional distress.

A belief that patients will wake up and be able to communicate just before dying. This misconception can result in long-lasting guilt when relatives are not able to be at the bedside at the moment of death.

The gurgling or crackling sounds of air passing over accumulated respiratory and oropharyngeal secretions, which are colloquially termed the “death rattle,” may be interpreted as dyspnea or choking by onlookers.

Increased airway secretions may interfere with a patient’s ability to sleep, worsen dyspnea, precipitate uncomfortable coughing spells, and predispose to infections. In the last stages of life, gurgling and crackling sounds as a result of increased secretions can result in distress to loved ones, who are often unaware that the sounds, often referred to as the “death rattle,” are a natural phenomenon. In addition to a health care professional explaining and reassuring the patient’s family that the noises are a natural occurrence of the dying process, proper positioning, allowing patients to suction the secretions when they have the capacity to do so, and anticholinergic medications (table 18) may help to minimize these secretions. Quaternary compounds, such as glycopyrrolate and scopolamine (hyoscine) butylbromide (which is only available outside of the United States), cause much less central effects as compared with tertiary amines such as atropine sulfate and scopolamine (hyoscine) hydrobromide. This subject is covered in more detail separately. (See "Palliative care: The last hours and days of life", section on 'Airway secretions'.)

The perception of distress or discomfort in dying patients is associated with increased risk of complicated bereavement in relatives and other loved ones [87]. Family caregivers reported significantly more observed behaviors (grimacing, groaning, shouting, touching or rubbing an area, purposeless movements, and labored breathing) and discomfort in unresponsive terminally ill cancer patients than did bedside nurses [88]. Education on expected symptoms and normal physiological changes at the end of life are needed reduce perceived level of distress by informal caregivers and, potentially, the burden of bereavement. (See "Grief and bereavement in adults: Clinical features" and "Grief and bereavement in adults: Management".)

Palliative sedation — For patients at the end of life, palliative sedation is a measure of last resort to alleviate severe symptoms that are refractory to other forms of treatment. It is most commonly utilized for pain, dyspnea, agitated delirium, and convulsions. It is performed by the administration of sedative medications (typically short-acting benzodiazepines) in monitored settings and is aimed at inducing a state of decreased awareness or absent awareness (unconsciousness). The intent of palliative sedation is to relieve the burden of otherwise intolerable suffering for terminally ill patients and to do so in such a manner so as to preserve the moral sensibilities of the patient, the medical professionals involved in their care, and concerned family and friends. (See "Palliative sedation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care" and "Society guideline links: Dyspnea".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Medical care during advanced illness (The Basics)" and "Patient education: Advance directives (The Basics)")

SUMMARY AND RECOMMENDATIONS

Most patients in the terminal phase of a serious and/or life-threatening illness, such as cancer, develop gradually worsening physical and psychosocial symptoms in the weeks and months before death (see 'Introduction' above). Terminally ill patients, particularly those with advanced cancer, often present with multiple symptoms simultaneously and are frequently severely asthenic and distressed. Periodic symptom reassessment is valuable for setting treatment goals, monitoring the response to specific symptomatic interventions, and communicating between members of the health care team. (See 'Symptom assessment' above.)

Fatigue is a common, typically multidimensional symptom, often with multiple contributing causes. Management includes treatment of reversible causes, if any are identified (table 5). If a specific cause cannot be identified, symptomatic management (ie, with a short trial of a glucocorticoid or methylphenidate) is appropriate. (See 'Fatigue' above.)

Opioids are the mainstay of therapy for cancer-related pain. (See 'Pain' above.)

For patients with nausea, if a potentially reversible cause cannot be identified and bowel obstruction is ruled out, symptomatic treatment with prokinetic agents, such as metoclopramide, is often helpful. (See 'Nausea with or without vomiting' above.)

Treatment of constipation initially starts with addressing underlying, potentially reversible factors (table 9). If a reversible cause cannot be identified and modified, symptomatic treatment, initially with senna, is appropriate. (See 'Constipation' above.)

Frequent oral hygiene is the first step in treating xerostomia. Rinsing with cold water, sucking on ice chips, chewing sugarless gum to increase salivation, and artificial saliva may provide comfort. Potentially beneficial approaches for patients who have radiation therapy-related xerostomia include acupuncture and oral pilocarpine. (See 'Xerostomia' above.)

The great majority of patients in the terminal phase of an advanced, serious, or life-threatening illness experience reduced oral intake because of loss of appetite, generalized weakness, nausea, vomiting, or impaired cognition. For the vast majority, there is no evidence that artificial nutrition prolongs life or improves functional status, and it is not indicated, particularly in those with cachexia-anorexia syndrome. (See 'Artificial nutrition and hydration' above.)

The possibility that dehydration or malnutrition may contribute to suffering and hasten death in patients at the end of life has generated strong debate, with arguments for and against parenteral fluid and nutrition administration. However, decisions regarding the use of parenteral hydration or nutrition should be individualized and involve the patient, family, other caregivers, and other health care professionals, with a careful assessment of potential benefits and drawbacks. (See 'Hydration in end-of-life care' above.)

Depression is the most common mental health problem encountered in palliative medicine, yet it is widely underdiagnosed and undertreated. Individuals who suffer from major depression are at high risk of suicide, and they may express to health care providers a desire for a hastened death. Failure to diagnose and treat major depression impairs the quality of life of dying patients and adds to their burden of suffering. (See 'Depression, suicidal ideation, and demoralization' above.)

Delirium is common in palliative care, and there are a number of contributing factors, especially opioids and other drugs. Initial management should include efforts to reverse precipitating causes and provide best supportive care for symptomatic distress associated with mild to moderate delirium. For persistent symptoms refractory to medical treatment of potential underlying etiologies, haloperidol is the drug of choice for pharmacologic management of medically ill patients with delirium, especially when there is evidence of psychomotor agitation, delusions, or hallucinations. (See 'Delirium' above.)

In the last hours of life, increased airway secretions may interfere with a patient’s ability to sleep, worsen dyspnea, precipitate uncomfortable coughing spells, increase caregiver distress, and predispose to infection. Reassuring the patient’s loved ones, proper positioning, allowing patients to suction the secretions when they have the capacity to do so, and judicious use of anticholinergic medications (table 18) may help to minimize these secretions. (See 'Last hours of life' above.)

Effective treatment will successfully alleviate the majority of symptoms that arise in terminally ill patients. Palliative sedation may be indicated for patients in the last stages of life who have refractory symptoms that cannot otherwise be alleviated by an interdisciplinary palliative care team. (See 'Palliative sedation' above.)

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Topic 2199 Version 59.0

References

1 : Comfort Care for Patients Dying in the Hospital.

2 : Early palliative care for patients with metastatic non-small-cell lung cancer.

3 : The uses of psychotropics in symptom management in advanced cancer.

4 : Autonomic failure in patients with advanced cancer.

5 : Patient assessment in palliative cancer care.

6 : Prognostic factors in patients with recently diagnosed incurable cancer: a systematic review.

7 : Systematic review of cancer presentations with a median survival of six months or less.

8 : Clinical signs of impending death in cancer patients.

9 : Randomized controlled trial of a prompt list to help advanced cancer patients and their caregivers to ask questions about prognosis and end-of-life care.

10 : The take-home message: patients prefer consultation audiotapes to summary letters.

11 : Impact of a family information leaflet on effectiveness of information provided to family members of intensive care unit patients: a multicenter, prospective, randomized, controlled trial.

12 : Written information given to patients and families by palliative care units: a national survey.

13 : Written information given to patients and families by palliative care units: a national survey.

14 : Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment.

15 : A pilot trial of decision aids to give truthful prognostic and treatment information to chemotherapy patients with advanced cancer.

16 : Comparing hospice and nonhospice patient survival among patients who die within a three-year window.

17 : Discussing prognosis: "how much do you want to know?" talking to patients who do not want information or who are ambivalent.

18 : Discussing prognosis: "how much do you want to know?" talking to patients who are prepared for explicit information.

19 : SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer.

20 : Discussions of Life Expectancy and Changes in Illness Understanding in Patients With Advanced Cancer.

21 : Intensive communication: four-year follow-up from a clinical practice study.

22 : A communication strategy and brochure for relatives of patients dying in the ICU.

23 : The needs of terminally ill cancer patients versus those of caregivers for information regarding prognosis and end-of-life issues.

24 : The dynamics of change: cancer patients' preferences for information, involvement and support.

25 : Evaluating an Intervention to Improve Communication Between Oncology Clinicians and Patients With Life-Limiting Cancer: A Cluster Randomized Clinical Trial of the Serious Illness Care Program.

26 : Effect of the Serious Illness Care Program in Outpatient Oncology: A Cluster Randomized Clinical Trial.

27 : Pharmacological treatments for fatigue associated with palliative care.

28 : Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer.

29 : A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer-Related Fatigue in Patients With Advanced Cancer.

30 : Assessment and management of chemical coping in patients with cancer.

31 : Random urine drug testing among patients receiving opioid therapy for cancer pain.

32 : The prevalence of bowel problems reported in a palliative care population.

33 : Exploring the relationship between the frequency of documented bowel movements and prescribed laxatives in hospitalized palliative care patients.

34 : Using the symptom monitor in a randomized controlled trial: the effect on symptom prevalence and severity.

35 : Constipation in Specialized Palliative Care: Prevalence, Definition, and Patient-Perceived Symptom Distress.

36 : Laxatives for the management of constipation in people receiving palliative care.

37 : Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients.

38 : A comparison of sennosides-based bowel protocols with and without docusate in hospitalized patients with cancer.

39 : Opioid Induced Constipation Part I: Established Management Strategies #294.

40 : Stimulant laxatives and opioid-induced constipation.

41 : The mouth and palliative care.

42 : The mouth and palliative care.

43 : Dietary patterns in patients with advanced cancer: implications for anorexia-cachexia therapy.

44 : Eating-related distress and need for nutritional support of families of advanced cancer patients: a nationwide survey of bereaved family members.

45 : Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in male patients with cancer.

46 : Medically assisted nutrition for palliative care in adult patients.

47 : Should patients with advanced, incurable cancers ever be sent home with total parenteral nutrition? A single institution's 20-year experience.

48 : The effect of total parenteral nutrition on the survival of terminally ill ovarian cancer patients.

49 : Parenteral hydration in patients with advanced cancer: a multicenter, double-blind, placebo-controlled randomized trial.

50 : Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.

51 : Special report from a symposium held by the World Health Organization and the World Federation of Sleep Research Societies: an overview of insomnias and related disorders--recognition, epidemiology, and rational management.

52 : Patient-reported sleep disturbance in advanced cancer: frequency, predictors and screening performance of the Edmonton Symptom Assessment System sleep item.

53 : Patient-reported sleep disturbance in advanced cancer: frequency, predictors and screening performance of the Edmonton Symptom Assessment System sleep item.

54 : A systematic review of the demoralization syndrome in individuals with progressive disease and cancer: a decade of research.

55 : A Review of the Construct of Demoralization: History, Definitions, and Future Directions for Palliative Care.

56 : Receiving palliative treatment moderates the effect of age and gender on demoralization in patients with cancer.

57 : The frequency and clinical course of cognitive impairment in patients with terminal cancer.

58 : Impact of delirium and recall on the level of distress in patients with advanced cancer and their family caregivers.

59 : Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care.

60 : Increasing anticholinergic burden and delirium in palliative care inpatients.

61 : The Memorial Delirium Assessment Scale.

62 : Clarifying confusion: the confusion assessment method. A new method for detection of delirium.

63 : Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial.

64 : Delirium at the end of life.

65 : A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients.

66 : Pharmacovigilance in hospice/palliative care: net effect of haloperidol for delirium.

67 : Haloperidol, risperidone, olanzapine and aripiprazole in the management of delirium: A comparison of efficacy, safety, and side effects.

68 : Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.

69 : Decreased extrapyramidal symptoms with intravenous haloperidol.

70 : Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial.

71 : Dyspnoea in patients with advanced cancer: incidence, causes and treatments.

72 : Disability, psychological distress and quality of life in breast cancer survivors with arm lymphedema.

73 : Understanding lymphoedema in advanced disease in a palliative care setting.

74 : Lower limb lymphedema: experiences and perceptions of cancer patients in the late palliative stage.

75 : Evaluation of the clinical effectiveness of physiotherapeutic management of lymphoedema in palliative care patients.

76 : Implementation of modified manual lymphoedema treatment-complex physical therapy (MLT-CPT) in terminal ill patient

77 : Is Kinesio taping useful for advanced cancer lymphoedema treatment?

78 : Is Kinesio taping useful for advanced cancer lymphoedema treatment?

79 : Care of palliative patients with cancer-related lymphoedema.

80 : Reflections on lymphoedema, fungating wounds and the power of touch in the last weeks of life.

81 : Reduction of edema of lower extremities by subcutaneous, controlled drainage: eight cases.

82 : The use of subcutaneous drainage for the management of lower extremity edema in cancer patients.

83 : Treatment of lower extremity edema by subcutaneous drainage in palliative care of advanced cancer patients.

84 : Use of closed controlled subcutaneous drainage to manage chronic lower limb oedema in patients with advanced cancer.

85 : Subcutaneous lymphatic drainage (lymphcentesis) for palliation of severe refractory lymphedema in cancer patients.

86 : Palliative care for cancer-related lymphedema: a systematic review.

87 : Terminal care: evaluation of effects on surviving family of care before and after bereavement.

88 : Perception of discomfort by relatives and nurses in unresponsive terminally ill patients with cancer: a prospective study.