Timothy C. Nichols, MD

• Professor of Medicine and Pathology and Laboratory Medicine
• Director, Francis Owen Blood Research Laboratory
• Division of Cardiology
• University of North Carolina School of Medicine
• Chapel Hill, North Carolina

While some depressive symptoms are frequent in cancer patients erectile dysfunction treatment lloyds pharmacy buy generic malegra fxt 140 mg online, only a minority of patients develop adjustment disorders and only a small percentage present with major depressive or anxiety disorders (Reeve et al doctor for erectile dysfunction in mumbai effective 140 mg malegra fxt. The diagnosis of a major depressive episode in patients with advanced-stage cancer is difficult because the patients frequently present with neurovegetative and somatic symptoms that are part of the disease itself impotence blog order malegra fxt from india. The diagnosis of major depression thus should rely more on the presence of psychological and cognitive signs and symptoms in these patients than in those without advanced-stage cancer (Chochinov erectile dysfunction treatment prostate cancer cheap malegra fxt 140 mg mastercard, 2001) (see Chapter 17 impotence nerve damage generic 140 mg malegra fxt with amex. Nevertheless, cancer patients presenting with an adjustment disorder or a major depressive disorder can have fatigue as one of the prevalent symptoms. One prospective cohort study of elderly patients with cancer found a significant association between the intensity of fatigue and psychological symptoms such as anxiety and depression (Respini et al. In a double-blind clinical trial of 94 women with breast cancer, depression was significantly reduced in the 44 patients receiving paroxetine compared to the Paraneoplastic neurological syndromes Paraneoplastic neurological syndromes are rare but are important to recognize, as many of these syndromes can precede the clinical 8. One study found that patients with breast cancer who had undergone adjuvant chemotherapy or autologous bone marrow transplantation appeared to experience fatigue for months to years after the completion of treatment (Cohen et al. Biological response-modifying agents have also been implicated in fatigue; for instance, interferon-alpha was shown to cause fatigue in 70% of patients (Jones et al. In fact, fatigue is the most frequent dose-limiting side effect in patients receiving biological response-modifying treatments for cancer (Aparicio et al. Opioids such as morphine have significant effects on the reticular system and are capable of inducing sedation, cognitive changes, and fatigue in some patients. In addition, anxiolytics, hypnotics, and other drugs may cause sedation and fatigue. Subacute necrotic myelopathy Mainly found in patients with lung cancer Peripheral paraneoplastic neurological syndrome Ascending acute polyneuropathy (Guillain­ Barré syndrome) Neuromuscular paraneoplastic syndromes Dermatomyositis, polymyositis Eaton­Lambert syndrome Associated with malignancy in about 50% of cases (onset within 1 year) Strongly associated with small cell lung cancer. Improves with successful treatment 30% of cases occur in patients with thymoma, while most of the rest occur in those with lymphoma Myasthenia gravis Source: data from Warenius, H. Genetics and cancer-related fatigue There is preliminary evidence that various single nucleotide polymorphisms of proinflammatory cytokine genes (which affect the gene expression levels) are associated with cancer-related fatigue (Barsevick et al. In summary, evidence clearly shows that fatigue is a complex, subjective, multidimensional syndrome that can be attributed to multiple causes. It is particularly important to note that not only cancer but also cancer treatments, cancer-related symptoms. Other cancer-related symptoms Various correlative studies have shown that fatigue is associated with pain, psychological symptoms such as anxiety and depression, dyspnoea, sleep disturbances, anorexia, and constipation (Echteld et al. Side effects of cancer treatment Treatments for both cancer and the symptoms and conditions caused by cancer can cause or aggravate fatigue. The mechanisms by which these treatment modalities cause fatigue are not fully understood. Radiotherapy can result in anaemia, diarrhoea, anorexia, and weight loss, and chemotherapy commonly causes anorexia, nausea, vomiting, and anaemia; all these events may contribute to fatigue. These tests are of very limited value in cancer care and research, as they are very difficult for patients with advanced-stage cancer to perform. A suitable alternative is measuring daily physical activity and fatigue by means of actigraphy (Berger et al. An actigraph can also be used to record and evaluate sleep quantity and quality, daytime activity levels, and napping. Conversely, Dimsdale and colleagues found no correlation between fatigue expression and actigraph measurements in healthy controls (Dimsdale et al. Task-related fatigue tests attempt to assess the fatigue induced by standard tasks. Another tool used in oncology, the Edmonton Functional Assessment Test (Kaasa et al. A full assessment therefore involves a careful systems review and psychological assessment, a detailed physical examination, and blood tests that would detect anaemia and electrolyte or endocrine abnormalities. Multiple causes should be suspected in all patients, and the possible impact of various factors should be weighed according to their severity. Assessment Fatigue is one of the most common and complex symptoms in patients receiving palliative care. Due to the lack of consensus on the definition of fatigue and limited understanding of the exact causative mechanisms, its measurement can be challenging (Jean-Pierre et al. The assessment of fatigue routinely should involve the evaluation of the severity of the fatigue; its onset, duration, and level of interference with everyday life; associated psychological or social problems; and possible underlying causes. Subjective measures of fatigue are generally considered to be the most relevant in clinical practice and in clinical trials. However, there are studies indicating that the short scales within these instruments have certain limitations (Knobel, et al. The unidimensional scale is useful for the routine assessment of the severity of fatigue in clinical practice, but these tools may only predominantly assess the physical impact of fatigue and not its mental and emotional dimensions. Multidimensional tools help us to understand various dimensions of fatigue, such as cognitive and emotional dimensions, in addition to the physical dimension. Tools that are multidimensional are generally preferred to those that are not because they give a broader picture of the problem and can highlight both general and specific management approaches that may benefit a specific patient. However, the trade-off is that it requires more time to administer the questionnaire. Examples of multidimensional tools used to assess fatigue include the Fatigue Questionnaire and Multidimensional Fatigue Inventory. Screening for fatigue Routine screening for fatigue using single-item screening for cancer-related fatigue has become more common in clinical practice as patients seldom report fatigue so as to avoid distracting the treating physician from the management of their disease. Guidelines of the National Comprehensive Cancer Network Fatigue Practice Guidelines Panel (Berger et al. The guidelines suggest that the screening data be used to designate the fatigue as mild, moderate, or severe (on a 0­10 numerical rating scale, with 1­3 considered mild, 4­6 moderate, and 7­10 severe). A patient diagnosed with mild fatigue would be re-evaluated on an ongoing basis, whereas patients diagnosed with moderate or severe fatigue would undergo more focused assessment and intervention. A recent study found that a fatigue score of 5 or more out of 10 indicated clinically significant fatigue (Butt et al. Alterations in fatigue over time may demonstrate a relationship with a particular factor. This temporal pattern underscores the importance of continuous assessment and monitoring of symptoms and signs, even in palliative medicine. In planning a therapeutic approach, it is also important to answer the following questions: 1. Are there therapeutic measures available that have a reasonable cost/benefit ratio An intervention may have the purpose of decreasing the intensity of fatigue, allowing the patient to express a maximal level of functioning with a stable level of fatigue, or both. In palliative care, the satisfactory treatment of a symptom such as fatigue does not mean that the symptom must be eliminated completely. In a given patient, it is often impossible to determine with certainty whether or not an identified problem is a major contributor to fatigue or simply coexists with the fatigue. For example, fatigue should be measured before and after correcting hypercalcaemia or treating anaemia. This can be done in a number of ways, including using a simple numerical scale. If the level of fatigue does not improve after correction of an underlying abnormality, it is clear that further treatment of that abnormality will not improve the fatigue in the future. Several pharmacological and non-pharmacological approaches may be effective in these patients, however, including those that reduce energy expenditure or levels of fatigue. Specific treatments may also be used to address underlying abnormalities believed to contribute to the fatigue of an individual patient. Non-pharmacological approaches Of the various treatment strategies, exercise has the strongest empirical support in patients with early cancer and cancer survivors, with several recent meta-analyses concluding that physical activity has a moderate beneficial effect on cancer-related fatigue (Cramp and Byron-Daniel, 2012). There is also some support for psychological interventions, with a meta-analysis showing a small to moderate beneficial effect (standardized mean difference in the range of 0. The modest effect sizes in the psychological studies may be a result of the fact that many did not include a cancer-related fatigue-related aim or hypothesis (Jacobsen et al. The few trials that explicitly focused on fatigue, providing education about fatigue and instruction in self-care, coping techniques, and activity management, were more effective than non-specific interventions (Jacobsen et al. Physical activity or exercise A recent Cochrane review confirmed the beneficial effects of exercise in the management of cancer-related fatigue (Cramp and Byron-Daniel, 2012). In a total of 56 studies in which 1461 participants received an exercise intervention and with 1187 control participants, exercise was seen to be statistically more effective than the control intervention (standardized mean difference, -0. Both aerobic and resistance exercises, such as brisk walking, cycling, swimming, and weight lifting, are helpful; at least one 30-minute episode per day (at least 150 minutes per week) has been shown to reduce fatigue levels. In relation to diagnosis, they found that exercise benefits patients with fatigue and breast and prostate cancer but not those with haematological malignancies. In addition, they found that aerobic exercise significantly reduced fatigue but that resistance training and alternative forms of exercise failed to reach significance. Further research is necessary to determine the most effective type (aerobic vs resistance), frequency, duration, and intensity of exercise in palliative care patients. There is limited evidence of beneficial effects of exercise in palliative care patients. In a recent randomized controlled study in advanced-stage cancer patients, 121 patients were referred to exercise and 110 were referred to usual care. After 8 weeks of a standardized 60-minute, twice-a-week intervention, no significant differences were found in the primary outcome of physical fatigue as assessed by a fatigue questionnaire. Statistically significant results were noted in the physical performance measures, including a shuttle walk test and a hand grip strength test; however, this study had a relatively lower adherence rate (69%) and a high dropout rate (36%) (Oldervoll et al. Although no level 1 evidence exists on the efficacy of exercise, exercise should be prescribed for patients with advanced-stage cancer, if appropriate, as exercise may be beneficial to maintain muscle mass and physical strength, which are commonly affected due to cachexia related to progressive cancer (Oldervoll et al. Exercise may further be beneficial in improving outcomes, including maintaining independence, self-reported physical functioning, well-being, self-esteem, and energy (Segal et al. Usually in cases of deconditioning, if appropriate, the physiotherapist can suggest suitable exercises and encourage increased activity, which may have beneficial effects from both physical and psychosocial perspectives. In addition, if the patient is immobile, a physiotherapist can perform passive movements that will help the patient maintain flexibility and decrease painful tendon retraction. Occupational therapists can allow patients to remain safe and increase their activity at home by providing such resources as ramps, wheelchairs and walkers, elevated toilets, safety devices for bathrooms, and hospital beds. In addition, these therapists can give patients and families useful tips that enhance mobility and help prevent further muscle atrophy, tendon retraction, and pressure ulcers. Acupuncture Several studies have been conducted using acupuncture as an intervention for cancer-related fatigue (Garcia et al. In this study, 75 patients were randomly assigned to usual care and 227 patients to acupuncture plus usual care. The difference in the mean General Fatigue score of the multidimensional fatigue inventory, which was the primary outcome, between those who received the intervention and those who did not was -3. The intervention also improved all other fatigue aspects measured by the Multidimensional Fatigue Inventory. Pharmacological treatments In patients with fatigue of unknown origin and those for whom specific treatment is not available, several non-specific pharmacological interventions have been proposed. Corticosteroids, megestrol acetate, other anti-cachexia agents, and psychostimulant drugs are the most studied of these interventions. Unfortunately, there is a lack of compelling data to support any of these approaches other than very short term treatment with corticosteroids. Corticosteroids Studies have suggested that corticosteroids decrease fatigue in patients with advanced-stage cancer (Moertel et al. The inhibition of tumour or tumour-induced substances, as well as central euphoriant effects, are potential mechanisms (Moertel et al. One potential mechanism of improvement of fatigue is by improvement of the physical symptoms commonly associated with cancer and treatment, such as pain, nausea, anorexia, dyspnoea, and drowsiness (Wilcox, 1984; Bruera et al. In a preliminary randomized, controlled, double-blind cross-over trial study of 31 patients with advanced-stage cancer, 32 mg/day of methylprednisolone was found to significantly improve subjective fatigue (P < 0. Patients frequently underestimate the side effect burden at the beginning of chemotherapy. In one study, only 8% of patients expected tiredness but 86% experienced it (Kirsh et al. This result suggests that many patients undergo treatment without sufficient information to develop realistic expectations about what that treatment entails. Counselling and informing the patient of the possible causes of fatigue and the types of therapeutic options available may allow the patient the opportunity to develop realistic expectations. As the disease progresses, the patient will be required to adapt to further limitations in physical functioning and activity; similarly, the family will need to have realistic expectations for the patient. In a recently concluded randomized, double-blind placebo-controlled study (Yennurajalingam et al. The mean (standard deviation) improvement in the Functional Assessment of Cancer Therapy­Fatigue subscale at day 15 was significantly higher in the dexamethasone group than in the placebo group (9 (10. However, the numbers of grade 3 and higher adverse effects did not significantly differ between dexamethasone and placebo groups at day 15 (17/62 vs 11/58, P = 0. Two other multicenter European trials have confirmed that corticosteroids can improve quality of life and reduce fatigue (Della Cuna et al. In addition, corticosteroids can cause metabolic abnormalities and serious long-term toxic effects, including osteoporosis, myopathies, and increased risk of infections. In addition, the best types and doses of corticosteroids as a treatment for fatigue have not been established. Psychostimulants Clinical experience with cancer patients indicates that psychostimulants promote a sense of well-being, decrease fatigue, and alleviate depression. Methylphenidate, a presynaptic norepinephrine (noradrenaline) and dopamine reuptake inhibitor, is the most researched psychostimulant drug used in the treatment of fatigue and other symptoms such as depression and sedation in patients with advanced-stage cancer (Minton et al. Methylphenidate has been used to manage opioid-induced sedation and depression in the palliative care setting (Bruera et al.

Results showed no significant difference in effectiveness or survival among the three drugs erectile dysfunction treatment vancouver purchase malegra fxt 140 mg visa. The study was not designed to show that this made a difference to the natural history of noisy breathing strongest erectile dysfunction pills buy malegra fxt canada. For the three drugs impotence questionnaire order 140 mg malegra fxt free shipping, death rattle became non-disturbing or disappeared after 1 hour in 42% erectile dysfunction doctors tucson az cheap 140 mg malegra fxt with visa, 42% impotence pumps buy cheap malegra fxt online, and 37% of cases, respectively, and further improved to 76%, 60%, and 68%, respectively at 24 hours before levelling off. Treatment appears to be more effective when started at lower initial rattle intensity (Wildiers et al. Gentle oral suction may be considered when secretions are in the oropharynx but the distress associated should not be overlooked. Death rattle may have a negative impact on staff, and some doctors and nurses may feel obliged to intervene despite the absence of any evidence that the natural history of noisy breathing is changed by medications (Wee et al. However, family members of dying patients may not be universally distressed by death rattle (Wee et al. Individualized treatment is recommended, taking into consideration the potential distress experienced by caregivers. Clinical approach Initial management of haemoptysis includes airway protection and volume resuscitation. The patient should be placed in a lateral decubitus position, with the bleeding side down. A detailed history should then be taken with complete physical examination, followed by laboratory investigations. Differential diagnoses include epistaxis, bleeding from the mouth or pharynx, haematemesis, and false haemoptysis (aspiration of blood) (Andersen, 2006). Baseline investigations include complete blood count, renal and liver function tests, prothrombin time, and activated partial thromboplastin time. Localization of the site and source of bleeding may define the best treatment for stopping the bleeding. Chest radiograph can identify the site of bleeding in 33­82% of cases of massive haemoptysis, in the form of a mass, pneumonia, atelectasis, or cavitary lesion. Diffuse alveolar haemorrhage typically appears as alveolar infiltrates on chest radiography (Sirajuddin and Mohammed, 2008). Bronchoscopy plays an important role in localization of the anatomical site of bleeding, isolation of the involved airway, control of bleeding and treatment of the underlying cause of haemoptysis. In massive, life-threatening haemoptysis, rigid bronchoscopy, rather than fibreoptic bronchoscopy, is more efficient in ensuring airway patency, and maintaining ventilation and clearance of secretions to improve visualization. A fibreoptic bronchoscope can still be useful, being introduced through the rigid scope to access the upper lobes and peripheral bronchi (Sakr and Dutau, 2010). Haemoptysis the volume of expectorated blood is often used to define the severity of haemoptysis, but there is no agreed cut-off point (see also Chapter 8. Various subjective terms have been used, describing haemoptysis as massive, major, exsanguinating, or life-threatening (Sakr and Dutau, 2010). Massive haemoptysis has been defined as the expectoration of more than 300 mL of blood in a single episode of haemoptysis (Qiu et al. Massive haemoptysis has also been defined as haemoptysis of over 500 mL within 24 hours, haemoptysis needing volume resuscitation, or haemoptysis causing airway obstruction and asphyxia. However, the amount of expectorated blood used by other authors to define massive haemoptysis ranged from 100 to 1000 mL/24 hours (Sakr and Dutau, 2010). In untreated massive haemoptysis, 80% of patients may die (Sirajuddin and Mohammed, 2008). Causes of haemoptysis, differential diagnoses the bronchial arterial supply and, to a lesser extent, the non-bronchial systemic arterial supply are responsible for the majority of cases of massive haemoptysis. In a minority, massive haemoptysis may also arise from pulmonary vessels (Sakr and Dutau, 2010). A majority of patients respond well to conservative medical therapy, with or without blood transfusion. A dark towel to cover the patient and dark basin for collecting blood helps to reduce the visual impact. Support and attention should be given to the family and people who witness the event. Where possible, treatment should be directed at the underlying causes of the haemoptysis, such as oncological treatment, antibiotic, antituberculosis or antifungal therapy, and correction of coagulopathy. Drugs such as non-steroidal anti-inflammatory agents or anticoagulant should be withheld. Systemic treatment includes oxygen, oral or intravenous tranexamic acid (Sakr and Dutau, 2010), aerosolized vasopressin in the dosage of 5 units of orthnithine-8-vasopressin for mild and moderate haemoptysis (Anwar et al. Endobronchial tumours could be treated with laser photocoagulation, argon plasma coagulation, or electrocautery (Sakr and Dutau, 2010). Immediate control of haemoptysis has been reported in 57­100% of patients (Sakr and Dutau, 2010). The most dreaded complications are neurological deficits, which could be reduced by cannulation of the target vessel beyond the origin of spinal branches (Sakr and Dutau, 2010). Surgery is reserved for cases of technical failure of arteriography, or when the patient is not fit for transfer to radiological intervention (Sakr and Dutau, 2010). Surgery is also performed as a definitive treatment, to prevent recurrence, as in aspergilloma (Sakr and Dutau, 2010). When the patient is unfit for surgery, percutaneous treatment such as radiofrequency ablation of lung cancer has been used to control severe haemoptysis (Baisi et al. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life Massive hemoptysis: an update on the role of bronchoscopy in diagnosis and management. A 44-year-old man with hemoptysis: a review of pertinent imaging studies and radiographic interventions. Management of fatal haemoptysis If a patient is at risk of massive haemoptysis, it is essential to establish an action plan in anticipation (see Chapter 8. The patient and family need to be informed, psychologically prepared, with possible treatment options discussed. If a massive life-threatening haemoptysis occurs, sedation to relieve the distress should be given as soon as possible. Zhu and Cynthia Wu Anaemia and cytopenias Introduction to anaemia and cytopenias the illnesses, malignant or benign, that bring patients to a palliative care setting are often complicated by haematological problems such as anaemia, bone marrow failure, disseminated intravascular coagulopathy, and thrombosis. Supportive therapy for these problems can provide gratifying relief of symptoms and improvement in overall quality of life. This chapter emphasizes a practical approach to assessment and therapy intended to maximize quality of life. These cytokines stimulate the uptake into and storage of iron in macrophages and monocytes while also preventing the export of iron out of these cells. This results in a paradoxical situation of iron-deficient erythropoiesis occurring in a marrow replete with iron. Simultaneously, the cytokines also suppress the ability of the kidneys to produce erythropoietin, enhance red blood cell membrane damage, and prevent the differentiation and proliferation of red cell progenitors in the marrow. Together, erythropoiesis is reduced resulting in anaemia (Weiss and Goodnough, 2005). The anaemia is typically normocytic, normochromic, and is usually mild to moderate (80­95 g/L). Anaemia Anaemia is present in 77% of men and 68% of women receiving palliative care (Dunn et al. Typical symptoms associated with a sudden drop in haemoglobin as seen with acute blood loss include tachycardia, orthostatic hypotension, and dyspnoea. If the onset of anaemia is more gradual, compensatory mechanisms can help lessen these symptoms by increasing the cardiac output, increasing plasma volume and shifting the haemoglobin dissociation curve. Patients can often remain symptom free if mild to moderate anaemia evolves gradually. More commonly, however, a diminished overall well-being is seen manifesting as fatigue, decreased exercise capacity, and decreased appetite. Some patients can also complain of dizziness, headache, syncope, tinnitus, vertigo, and impaired cognitive function. Patients with underlying cardiac disease are more susceptible to anaemic symptoms as they are unable to compensate as readily (Mercadante et al. Determining the cause of anaemia in the palliative care setting can be challenging, since the aetiology is often multifactorial. Disease-related causes include bone marrow infiltration, blood loss, haemolysis, and anaemia of chronic disease. Cancer-related treatment can also result in anaemia such as myelosuppression from chemotherapy and treatment-related myelodysplastic syndrome. Concomitant factors such as folate deficiency from malnutrition and gastrointestinal resections can also contribute to anaemia (Mercadante et al. Acute and chronic haemorrhage Acute and chronic blood loss is common in a palliative patient, especially in gastrointestinal, head and neck, respiratory, uterine, and urinary cancers. Bulky sarcomas, hepatomas, melanomas, and ovarian cancers can bleed into the malignant masses as well (Mercadante et al. Even the loss of a few millilitres of blood a day can result in iron deficiency over time. In the early stage of iron deficiency, iron stores are low resulting in a reduced ferritin but normal serum iron, iron saturation, and haemoglobin levels. As iron deficiency worsens, serum iron and iron saturation falls but the haemoglobin is preserved. Anaemia is the end result of severe iron deficiency with the presence of microcytic hypochromic red blood cells. Abnormally shaped cells like target cells and pencil cells are seen as the severity of the iron deficiency advances (Beutler, 2010). Fruits and vegetables are rich in folic acid and the recommended dietary intake for an adult is 0. When folic acid intake is reduced to less than 5 micrograms, megaloblastic anaemia ensues in approximately 4 months. Folic acid is absorbed in the duodenum and proximal jejunum so patients with intestinal resections or masses involving this area are at high risk of developing megaloblastic anaemia. Megaloblastic anaemia results in enlarged megaloblastic bone marrow precursor cells and consequently enlarged red blood cells increasing the red cell volume. Hypersegmented neutrophils with the presence of more than the usual three to five nuclei lobes are classically described in megaloblastic anaemia. All cell lines can be affected resulting in anaemia, thrombocytopenia, and/or neutropenia. Typically 1 mg a day is adequate to correct anaemia even if malabsorption is present (Green, 2010). The first step in management of haemorrhage is to control the bleeding lesion if practical (see Chapter 8. This may be accomplished surgically, endoscopically, or by radiation of the bleeding lesion (Videtic, 2013). Iron supplementation should be started concomitantly if iron deficiency is present. Treatment can be provided either orally in the form of simple iron salts or parentally as iron­carbohydrate complex. The oral route is preferred as parenteral iron is associated with more severe adverse effects. Mild gastrointestinal side effects like nausea, heartburn, constipation, or diarrhoea are common. For these patients, changing to another form of iron or reducing the dose initially can be helpful (Beutler, 2010). Parenteral iron is useful for patients who are intolerant of oral iron, have intestinal malabsorption issues, or may be losing iron more quickly than can be replaced with oral supplementation. The total dose required can be calculated by this formula: Dose of iron (mg) = whole-blood haemoglobin deficit (g/dL) × body weight (lb) Iron sucrose contains 20 mg of elemental iron per millilitre and is recommended by the manufacturer to be administered at a maximum of 100 mg three times weekly. However, it has been safely given to chronic kidney disease patients at doses of 500 mg over 3 hours on 2 consecutive days. Typical adverse effects include hypotension, cramps, nausea, headache, vomiting, and diarrhoea (Beutler, 2010). Iron dextran contains 50 mg of elemental iron per millilitre and is recommended by the manufacturer to be administered at a maximum of 100 mg per dose preceded by a 0. Larger doses are frequently used and considered safe with an increase in minor adverse effects. Iron dextran can result in a severe anaphylactic reaction occurring in less than 1% of patients. It is not dose dependent so can occur within the first few millilitres of the infusion. Typical presentation includes difficulty breathing, a choking sensation, becoming sweaty and anxious, nausea, and vomiting within the first few minutes of starting the iron dextran infusion. The infusion should be stopped immediately, resuscitation initiated, and epinephrine (adrenaline) be readily available. For patients with severe anaemia, transfusions may be necessary to help boost their haemoglobin. As each millilitre of blood contains 1 mg of elemental iron, blood transfusions will also help boost iron stores as well. Bone marrow infiltration While anaemia from metastatic cancer is most commonly related to anaemia of chronic disease, iron deficiency, or other nutritional deficiencies, bone marrow infiltration from metastatic disease can occur. All malignancies can metastasize to the marrow, but the most common are from the lung, breast, and prostate. While not common, the classic clinical picture is that of a leucoerythroblastic blood picture with the presence of immature nucleated red cells, myeloid white cell precursors, and teardrop-shaped red cells. A bone marrow biopsy can help to confirm the diagnosis but since the majority of metastatic malignancies with marrow involvement are incurable, it is oftentimes not clinically necessary (Agarwal and Prchal, 2010).

Although most of the full agonist drugs are well absorbed by subcutaneous infusion buy generic erectile dysfunction drugs buy cheap malegra fxt line, some (like morphine tartrate erectile dysfunction testosterone purchase malegra fxt with visa, hydromorphone erectile dysfunction causes cancer generic malegra fxt 140 mg buy line, and diamorphine) are more suitable by virtue of their high solubility and low irritability kidney disease erectile dysfunction treatment buy malegra fxt master card. Methadone and fentanyl may produce significant local irritation when administered by the subcutaneous route erectile dysfunction pump infomercial generic 140 mg malegra fxt mastercard. For cultural and aesthetic reasons, the subcutaneous route is often preferred to rectal administration. Subcutaneous infusion may be also preferable in patients at the end of life because it is less disruptive than using intermittent analgesic suppositories when nursing a sick patient. Routes of administration Opioids should be administered by the least invasive and safest route capable of providing adequate analgesia. In a survey of patients with advanced cancer, more than half required two or more routes of administration prior to death, and almost a quarter required three or more (Lehmann and Zech, 1992). Oral administration the oral route of opioid administration remains the most important and appropriate in routine practice. Orally administered drugs have a slower onset of action, a delayed peak time, and a longer duration of effect compared with parenterally administered drugs. For most normal-release oral formulations, peak effect is typically achieved within 60 minutes. The oral route of drug administration is inappropriate for patients who have impaired swallowing or gastrointestinal obstruction, and for some patients who require a rapid onset of analgesia. For patients who require very high doses, the inability to prescribe a manageable oral opioid regimen may be an indication for the use of a non-oral route. When given orally, the opioids differ substantially with respect to their relative analgesic potency compared with parenteral administration. To some extent, this reflects differences in pre-systemic metabolism, that is, the degree to which they are inactivated as they are absorbed from the gastrointestinal tract and pass through the liver into the systemic circulation. Methadone, levorphanol, and oxycodone are subject to less pre-systemic elimination and also demonstrate a lower oral-to-parenteral potency ratio of at least 1:2. Failure to recognize these differences may result in a substantial reduction in analgesia when a change from parenteral to oral administration is attempted without upward titration of the dose, or toxic effects when changing in the opposite direction. Response to previous trials of opioid therapy It is always important to review the response to previous trials of opioid therapy. If the current opioid is well tolerated, it is usually continued unless difficulties in dose titration occur or the required dose cannot be administered conventionally. If dose-limiting side effects develop, a trial of an alternative opioid should be considered as discussed in the section on adverse effects. Coexisting disease Pharmacokinetic studies of pethidine, pentazocine, and propoxyphene have revealed that liver disease may decrease the clearance and increase the bioavailability and half-lives of these drugs (Kaiko et al. Mild or moderate hepatic impairment has only a minor impact on morphine clearance (Eddy and Lee, 1959); however, advanced disease may be associated with reduced elimination (Hermens et al. Patients with renal impairment may accumulate the active metabolites of propoxyphene (norpropoxyphene), pethidine (norpethidine), and morphine (M6G). Particular caution is required in the administration of these drugs to such patients (Hess et al. Until more data are available, it may be wise to assume that other opioids with active metabolites may produce similar problems of toxicity in patients with impaired renal 9. Rectal suppositories containing morphine, hydromorphone, oxymorphone, and oxycodone are available. The pharmacokinetics and bioavailability of drugs given rectally may differ from that of oral administration because of delayed or limited absorption and partial bypassing of pre-systemic hepatic metabolism. In practice, however, the potency of opioids administered rectally is approximately equal to that achieved by oral dosing (Varvel et al. In contrast with morphine, rectal oxycodone appears to have a delayed absorption and prolonged duration of action. For many patients, the rectal route is not used because it is more convenient to convert directly to a subcutaneous infusion of opioid using a portable syringe driver or similar device. Parenteral administration Bolus injections via parenteral routes of administration are considered for patients who have impaired swallowing or gastrointestinal obstruction, those who require a rapid onset of analgesia, and those who require very high doses that cannot be conveniently administered by other methods. Intravenous bolus provides the most rapid onset; the time to peak effect correlates with the lipid solubility of the opioid, ranging from 2 to 5 minutes for methadone and from 10 to 15 minutes for morphine. Although repeated intramuscular injections are commonplace in some countries, they are painful and offer no pharmacokinetic advantage, and their use is not recommended (Lehmann and Zech, 1992; Caraceni et al. Repeated bolus doses, if required, can be accomplished without frequent skin punctures by using an indwelling intravenous or subcutaneous infusion device. The discomfort associated with this technique is partially related to the volume to be injected; it can be minimized by the use of concentrated formulations. Studies suggest that dosing with subcutaneous administration can proceed in a manner identical to continuous intravenous infusion: a postoperative study comparing patients who received an identical dose of morphine by either intravenous or subcutaneous infusion found no difference in blood levels (Payne et al. To maintain the comfort of an infusion site, the subcutaneous infusion rate should not exceed 5 mL/hour. Subcutaneous infusion has become the first choice when parenteral analgesia is required in palliative care patients. Continuous intravenous infusion may be the most appropriate way of delivering an opioid for patients with a pre-existing implanted central line, when there is a need for infusion of a large volume of solution, or when using methadone. If continuous intravenous infusion must be continued on a long-term basis, a permanent central venous port is recommended. Continuous infusions of drug combinations may be indicated when pain is accompanied by nausea, anxiety, or agitation. In such cases an antiemetic, neuroleptic, or anxiolytic may be combined with an opioid provided that it is non-irritant, miscible, and stable in combined solution. As noted later in the text, a variety of different combinations of drugs are commonly given by continuous infusion (Fine et al. The compatibility of drug combinations is dependent on a number of factors, including the types of drugs, the concentrations of drugs, the diluent and temperature, and ultraviolet light. Generally infusions should contain as few drugs as possible, preferably no more than three. The absence of precipitation within a drug mixture is not synonymous with compatibility between the drugs in that mixture (Farrar et al. Epidural, intrathecal, and intraventricular administration the discovery of opioid receptors in the dorsal horn of the spinal cord led to the development of intraspinal opioid delivery techniques. In general, they provide a longer duration of analgesia at doses lower than required by systemic administration. The delivery of low opioid doses near the sites of action in the spinal cord may decrease supraspinally mediated adverse effects (see Chapter 13. Hydrophilic drugs, such as morphine and hydromorphone, have a prolonged t½ in cerebrospinal fluid and significant rostral redistribution (Christie et al. Lipophilic opioids, such as fentanyl and sufentanil, have less rostral redistribution and therefore fewer prolonged adverse effects if these become a problem. The addition of local anaesthetic such as bupivacaine to an epidural or intrathecal opioid has been demonstrated to improve analgesia without increasing toxicity (Faull et al. Continuous subcutaneous infusion using a portable battery-operated syringe driver or other similar device was originally devised to administer infusions of desferrioxamine to patients with thalassemia, but was subsequently used to deliver diamorphine to patients with advanced cancer who were unable to take oral drugs (Megens et al. This technique is now well established in palliative care and is used to administer analgesics, antiemetics, anxiolytic sedatives, and dexamethasone. A variety of devices have been employed, all designed to be lightweight and portable, and in one case, disposable. Opioids suitable for continuous subcutaneous infusion must be soluble, well absorbed and non-irritant. The initial conversion of opioid dose from systemic subcutaneous diamorphine or morphine is: epidural-1/10 of systemic dose intrathecal-1/10 of epidural dose. Topical There are several case series and one very small randomized controlled trial that examine the role of topical morphine for local analgesia. The small amount of existing evidence seems to point to a role in some situations, for example, cutaneous ulcers or tumour with cutaneous inflammation. Doses of 10­40 mg of morphine are used in simple gel, saline soaks, or local anaesthetic gel (Bullingham et al. Randomized controlled trials in non-malignant cutaneous pain, for example, burns or photodynamic therapy, have been negative. Thus, if a patient were on 100 mg of subcutaneous morphine or diamorphine/day, the equivalent epidural dose would be 10 mg, and the equivalent intrathecal dose would be 1 mg/day. Changing the route of administration As described earlier, when changing from the oral to parenteral routes, or vice versa, an adjustment in dose is required to avoid either toxic effects or a reduction in analgesia. There is considerable variation between patients, and upward or downward adjustment may then be required for individual patients. The slower onset of analgesia after oral administration often requires some adaptation on the part of a patient who is accustomed to the more rapid onset seen after parenteral opioid. In some patients, the problems associated with switching from the parenteral to the oral route of opioid administration may need to be minimized by slowly reducing the parenteral dose and increasing the oral dose over a 2­3-day period. Usually, no dose adjustment is required when patients are switched from the subcutaneous to the intravenous route or vice versa. The initial solution used for intrathecal infusion is normally around 1/10 of the above, that is: 1 mL 0. Hydromorphone is sometimes preferred to morphine for use in programmable intrathecal pumps because of incompatibility between some of the commonly-used devices and morphine. There are no clinical studies comparing the intrathecal and epidural routes in cancer pain. The epidural route is sometimes preferred because the techniques to accomplish long-term administration are simpler. A combined analysis of adverse effects observed in numerous trials of epidural or intrathecal administration suggests that the risks associated with these techniques are similar. The potential morbidity associated with these procedures emphasizes the need for a well-trained clinician and long-term monitoring for individual patients. Limited experience suggests that the administration of an opioid into the cerebral ventricles can provide long-term analgesia in selected patients. This technique has been used for patients with upper-body or head pain or with severe diffuse pain. Schedules have included both intermittent injection via an Ommaya reservoir and continual infusion using an implanted pump. The indication for the spinal routes of administration of opioid analgesics in palliative care patients is discussed in more detail in Chapter 13. However, clinical vigilance is required in patients with no previous opioid exposure and those administered drugs with long half-lives. With methadone, for example, delayed toxicity may develop as plasma concentration rises slowly towards steady-state levels. The integration of scheduled dosing with rescue doses provides a method for safe and rational stepwise dose escalation and is applicable to all routes of opioid administration. The rescue drug is typically identical to that administered on a continuous basis, with the exception of transdermal fentanyl and methadone; the use of an alternative short-t½ opioid is recommended for the rescue dose when these drugs are used. The frequency with which the rescue dose can be administered depends on the time to peak effect for the drug and the route of administration. Oral rescue doses can be offered up to Other routes and modes of administration Transdermal As previously described, fentanyl and buprenorphine are available in a transdermal formulation and their use is discussed above. Sublingual Sublingual absorption could potentially occur with any opioid, but bioavailability is very poor with drugs that are not highly lipophilic (Rance, 1979; Hoskin and Hanks, 1991). A sublingual preparation of buprenorphine is available in some countries, although not in the United States. Anecdotally, sublingual morphine has also been reported to be effective; given the poor sublingual 9. Clinical experience suggests that the size of the rescue dose should usually be equivalent to one-sixth of the 24-hour baseline dose, that is, the same as the 4-hourly dose of opioid. The magnitude of the rescue dose should be individualized and some patients with low baseline pain but severe exacerbations may require rescue doses that are substantially larger. As discussed in this chapter, in the setting of clinical trials where rescue doses are individualized, the effective doses rarely turn out to be one-sixth of the 24-hour dose. Scheduling with sustained-release formulations Sustained-release formulations can reduce the inconvenience associated with around-the-clock administration. These formulations should not be used for rapid titration of the dose in patients with severe pain. Sustained-release oral morphine sulphate and oxycodone, and transdermal fentanyl are now widely used, and sustained-release formulations of codeine, tramadol, and hydromorphone have been introduced in various countries. A normal-release formulation of a short-t½ opioid (usually the same drug) is often used as the rescue medication. Sustained- and normal-release formulations of oral morphine are dose equivalent; switching from one to the other is done on a milligram-for-milligram basis after the daily dose requirement is identified using a normal-release formulation. Because analgesic response to opioids increases linearly with the logarithm of the dose, dose escalations of less than 30­50% are not likely to improve analgesia significantly. Clinical experience indicates that a dose increment of this order of magnitude is safe and is large enough to observe a meaningful change in effects. In most cases, gradual dose escalation identifies a favourable balance between analgesia and side effects which remains stable for a prolonged period. While doses can become extremely large during this process, the absolute dose is immaterial as long as the balance between analgesia and side effects remains favourable. In a retrospective study of 100 patients with advanced cancer, the average daily opioid requirement was equivalent to 400­600 mg of intramuscular morphine, but approximately 10% of patients required more than 2000 mg and one patient required over 30 000 mg every 24 hours. Other centres have generally reported lower doses; a median dose of 60 mg/day in one centre and 120 mg/day in another (Hammersley et al. The regular dose can then be adjusted according to how many rescue doses have been given.

Psychological issues Anxiety erectile dysfunction drug therapy order malegra fxt toronto, depression what causes erectile dysfunction in 30s malegra fxt 140 mg visa, and psychological distress can all contribute to fatigue (Yennurajalingam et al erectile dysfunction drugs gnc best purchase malegra fxt. However erectile dysfunction homeopathic order malegra fxt now, the authors suggested that perhaps larger trials may be able to detect a significant difference between methylphenidate and placebo erectile dysfunction age 40 140 mg malegra fxt visa. They observed that the under-powering of the studies due to small sample sizes could have resulted in the lack of statistically significant difference between the methylphenidate and placebo. However, since the publication of the meta-analysis, larger studies using long-acting methylphenidate (Moraska et al. On the basis of these findings and preliminary data showing some trends of benefit in fatigued patients with depression or anxiety, the authors concluded that future studies are needed to explore the benefits of psychostimulants in a subset of fatigued patients with a predominance of depressed mood or sedation (Bruera, 2013; Bruera et al. Modafinil, whose mechanism of action is postulated to be via enhanced catecholaminergic signalling and decreased gamma aminobutyric acid release, primarily at the anterior hypothalamus, has also been shown to have benefits for the treatment of severe fatigue (Jean-Pierre et al. This agent also reduces fatigue in healthy individuals during sustained mental work and may have fewer side effects than D-amphetamine (Rammohan et al. Progestational agents Preliminary studies involving terminally ill patients have demonstrated rapid (within 10 days) improvement in fatigue and general well-being in patients treated with megestrol acetate at a dose of 160­480 mg/day as compared to patients receiving the placebo, without any significant change in nutritional status (Bruera et al. The mechanism of action by which progestational agents confer these benefits is unclear, although it is believed to be related to glucocorticoid or anabolic activity, as well as effects on cytokine release. A randomized controlled study showed that megestrol improves appetite and fatigue and has a better safety profile than corticosteroids. However a meta-analysis of four clinical studies of progestational agents showed no benefit of progestational agents compared with placebo for treating cancer-related fatigue (Minton et al. Other agents of potential benefit in the management of cachexia Other pharmacological agents that have potential benefit in the management of cachexia, such as thalidomide and omega-3 fatty acids, may also have a beneficial effect on fatigue. Aspirin and other non-steroidal anti-inflammatory agents have been investigated for the treatment of cancer-related symptoms, more specifically in the management of cachexia (Madeddu et al. There is evidence that these agents were associated not only with reduction of inflammatory markers associated with the cachexia but also with improvement of function and alleviation of quality of life (Madeddu et al. However, further studies are needed to determine whether treatment of these agents will result in clinically effective improvement of fatigue. Treatment/management of underlying factors As previously discussed, fatigue is often multicausal and may appear as a consequence of other conditions, such as cachexia, infection, or anaemia (Yennurajalingam and Bruera, 2007). Any intervention capable of reversing an underlying contributor should alleviate fatigue. Thus, it is useful to consider all factors that may be contributing to fatigue in any given patient, with the aim of identifying and treating reversible causes. It is also important to remember that reversible causes, such as dehydration, metabolic disorders, or severe anaemia, may coexist with non-reversible causes. Psychological factors Counselling should be considered for patients with adjustment disorders, depression, anxiety, and coping difficulties. Various randomized clinical trials have shown that supportive interventions (group and individual), such as education and stress management groups, coping strategies training, and behavioural interventions, can help cancer patients manage their fatigue (Homsi et al. As in the general population, the choice of antidepressant in a patient with advanced-stage cancer will depend on other patient factors. Selective serotonin reuptake inhibitors are commonly used and have fewer side effects than tricyclic antidepressants. An alternative is to consider using a psychostimulant, such as methylphenidate or modafinil, to treat the depression. Psychostimulants have been found to be effective antidepressants and are also useful in the treatment of opioid-induced sedation (Parker and Brotchie, 2010). An advantage of psychostimulants is their rapid antidepressant effect, which is usually apparent within a few days. Disadvantages include their neurotoxic side effects and the risk that patients will develop tolerance or dependency. Anaemia In patients with anaemia, determining the underlying cause is important, as it may influence the choice of treatment (see Chapter 8. As noted earlier, there is evidence that patients with less severe anaemia also benefit from increases in haemoglobin levels from the use of an erythropoietic-stimulating agent with chemotherapy (Demetri et al. The main disadvantages of erythropoietic-stimulating agent include its cost, recent evidence that it may cause increased thrombotic events, suggestions that it may reduce survival times (Fishbane and Jhaveri, 2012), and the delay of 4­8 weeks until an increase of 1­2 g/dL in haemoglobin concentration, with resulting symptomatic improvement, can be observed. These disadvantages are particularly relevant in palliative care patients who have a short life expectancy. Although treatment of anaemia has been shown to decrease fatigue in patients receiving chemotherapy, the correction of anaemia in patients with advanced-stage cancer at the end of life was found to have a limited impact on the intensity of fatigue (Stone et al. This is probably due to the fact that multiple factors contribute to fatigue in these patients, including cachexia, depression, pain, and deconditioning. Sleep disturbances Daytime sleepiness and sleep disturbances have been reported to influence the cancer related fatigue (Berger and Mitchell, 2008; Liu et al, 2012) (see Chapter 8. Further studies are warranted, especially those targeting common underlying mechanisms such as inflammation (Liu et al. Metabolic disorders Metabolic disorders, such as hypercalcaemia, hyponatremia, hypomagnesaemia, and hypokalaemia, should be corrected where possible. Hypogonadism affects two-thirds of men with advanced-stage Autonomic failure Autonomic failure in patients with diabetes and neurological disorders has been effectively managed by midodrine, a specific alpha 8. Low testosterone in men with cancer is associated with fatigue, anorexia, depression, and insomnia. Testosterone replacement therapy can be considered for patients with hypogonadism. A preliminary placebo-controlled study in 26 evaluable patients with hypogonadic advanced-stage cancer (bioavailable testosterone levels of 70­270 ng/dL) showed a trend towards improvement in the fatigue scores after 4 weeks of treatment using intramuscular testosterone (Pulivarthi et al. Larger prospective studies are needed to look at the effects of testosterone replacement in cancer patients with fatigue and to determine which of these patients are most likely to benefit from treatment. Dehydration and hypoxia should be managed as appropriate, and the treatment of underlying cardiac or respiratory conditions should be optimized. However, further studies are needed in palliative care population to determine the effectiveness and safety of standardized nutritional supplements in patients receiving palliative care. Drug induced the list of prescribed drugs should be monitored regularly to ensure that the fatigue is not an iatrogenic effect. Fatigue is a common complication of cancer-specific therapy including cytotoxic therapy, radiation therapy, hormonal therapy, surgery, and targeted therapy, and this adverse effect may be dose related. Nutritional support (enteral and/or parenteral) Studies in patients with advanced cancer suggest that there is limited evidence to suggest that artificial nutrition improves patient survival, performance status, quality of life, treatment toxicity, or psychological well-being. Further studies are needed to determine which subset of palliative patients would benefit from nutritional support so as to improve fatigue and quality of life (Chermesh et al. Nutritional deficiencies Studies have found that the micronutrient carnitine is frequently deficient in patients with advanced-stage cancer, and preliminary studies using escalating doses (250­3000 mg/day) of carnitine supplementation have shown improvements in fatigue. However, a recent randomized controlled study for the treatment of fatigue in 376 cancer patients showed that 2 g/day of L-carnitine did not significantly improve fatigue compared to a placebo (Cruciani et al. Multimodal therapy Symptomatic treatment of fatigue should be considered in cases in which fatigue is not effectively managed by treatment of reversible causes (Yennurajalingam and Bruera, 2007). In these cases, due to the multidimensional nature of fatigue, it is unlikely that fatigue can be effectively treated using a single intervention. A combination of pharmacological and non-pharmacological treatments should be considered on the basis of a predominant pathophysiological mechanism for a given patient (Bruera and Yennurajalingam, 2010). Similarly, various combinations of treatment that have shown preliminary beneficial effects on fatigue in patients with advanced-stage cancer should be considered on an individual basis. These may include interventions such as cognitive behavioural therapy, educational interventions, anti-inflammatory drugs, and exercise. However, further studies using sound research methodology are needed to investigate the efficacy of multimodal intervention in patients with fatigue. Nutritional supplements Various nutritional supplements such as Ginseng quinquefolius (American ginseng), Paullinia cupana (guarana), co-enzyme Q10, and L-carnitine, have been investigated in cancer patients to manage fatigue with various levels of success. Three hundred and sixty-four participants were enrolled from 40 institutions in United States. Changes from baseline in the general subscale of the Multidimensional Fatigue Symptom Inventory-Short Form were 14. Greater benefit was reported in patients receiving active cancer treatment vs those who had completed treatment. In another study by de Oliveira Campos and colleagues, patients with progressive fatigue after their first cycle of chemotherapy were randomized to receive either Paullinia cupana (guarana) 50 mg by mouth twice daily (32 patients) or placebo (43 patients) for 21 days (de Oliveira Campos, 2011). After a 7-day washout period, patients Conclusion Fatigue in cancer patients is now accepted as a symptom that should be studied in its own right. Unfortunately, few studies have addressed fatigue in palliative cancer populations. Consequently, most of the insight into the complexity of fatigue must be based upon extrapolation from studies performed with patients earlier in the disease trajectory. To improve treatment, we must gain a better understanding of the many aspects of fatigue. Thus, identifying the pathophysiological mechanisms that cause fatigue is important. Assessment and staging tools that are valid and reliable are needed to assist in clinical practice and research. Clinical syndromes of fatigue (cognitive, affective, and physical) also must be better characterized. Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial. Physical exercise for cancer patients with advanced disease: a randomized controlled trial. The potential of agents such as eicosapentaenoic acid, thalidomide, and anabolic steroids must be explored in studies in which fatigue is a primary endpoint. Finally, the role of psychostimulants should be further researched, and the importance of counselling, rest, and exercise in cancer patients receiving palliative care should be clarified. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. Sham Introduction to dyspnoea and other respiratory symptoms in palliative care A breath is a vital sign of a living creature. Hence a breath may be filled with physiological, psychological, and spiritual signals. Breathlessness serves as a warning signal in responding to the metabolic demand on a person. When the respiratory system is compromised by diseases, every breath may become laborious. Every day, millions of people throughout the world are distressed by breathlessness and other respiratory symptoms. Dyspnoea becomes an important factor predicting the will to live in the terminally ill while approaching death (Chochinov et al. Relieving distress related to respiratory symptoms is key to addressing suffering. In a cohort of 5682 palliative care patients, breathlessness increased from around 50% at 3 months before death to 65% at the time of death, with severe breathlessness increased from less than 10% to 26% at the two time points respectively. Two patterns of dyspnoea have been reported by cancer patients: the breakthrough-only dyspnoea in 61%, and constant dyspnoea in 39% of patients, among which 20% presented as breakthrough episodes (Reddy et al. The majority of patients with breakthrough episodes presented with fewer than five episodes daily, with each episode frequently lasting for less than 10 minutes. Episodic breathlessness could be triggered by exertion, emotion, or environment; or occur spontaneously without trigger. However, episodic breathlessness was only reported as a primary outcome in eight among 27 studies (Simon et al. Dyspnoea along the trajectory of life-limiting illnesses has been evaluated by several longitudinal studies. The experience is derived from interactions among physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioural responses. Perception entails conscious recognition and interpretation of sensory stimuli and their meaning (Parshall et al. Dyspnoea is a term we use for a symptom that patients often describe as breathlessness. Dyspnoea prevalence, pattern, and trajectory Dyspnoea is common among patients with advanced cancers and non-cancer life-limiting illnesses. The prevalence of dyspnoea varies with the site of primary cancers and the stage of illness. Similar to the pain model, it is postulated that dyspnoea consists of multiple dimensions, including the independent component of sensory dimension (sensory intensity and sensory quality), immediate affective stage which trigger immediate behaviour, and a stage of cognitive evaluative and emotional response which affects long-term behaviour (Lansing et al. Against the traditional neurochemical and neuromuscular model, a neuromatrix-gated model has been proposed to unify multiple factors by recognizing different inputs from afferents at receptor levels and inputs from different areas of the brain (Williams, 2011). Patients with non-cancer diagnoses had significantly higher levels of breathlessness at all three time points, while cancer patients had less breathlessness initially but increased significantly at day 10 and day 3 before death. In another cohort of over 10,000 cancer patients, the trajectories of performance status and symptom scores during the last 6 months of life were evaluated (Seow et al. Breathlessness increased in severity over time, particularly in the month before death. Qualities of dyspnoea and neurophysiology There are at least three separate qualities of dyspnoea: air hunger or unsatisfied inspiration; work or effort; and tightness (Lansing et al. This classification depends on different perceptual qualities with distinct afferent sources: 1. Air hunger or unsatisfied inspiration: this is the conscious perception of the urge to breathe.

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