Symptoms During the Final Months, Weeks, and Days of Life
The available evidence provides some general description of frequency of symptoms in the final months to weeks of the end of life (EOL). However, when the results of published studies of symptoms experienced by patients with advanced cancer are being interpreted or compared, the following methodological issues need to be considered:
- Variation in the instrument used to assess symptoms and/or severity of symptoms.
- Variation in the timing of symptom assessment and whether the assessments were repeated over time.
- Population studied in terms of specific cancers, or a less specified population of people with cancer.
- Whether patients were recruited in the outpatient or inpatient setting.
- Whether specialized palliative care services were available.
Results of one of the larger and more comprehensive studies of symptoms in ambulatory patients with advanced cancer have been reported. Ambulatory patients with advanced cancer were included in the study if they had completed at least one Edmonton Symptom Assessment System (ESAS) in the 6 months before death. The ESAS is a patient-completed measure of the severity of nine symptoms (anxiety, lack of appetite, depression, drowsiness, nausea, pain, shortness of breath, tiredness, and well-being). Analysis of the changes in the mean symptom intensity of 10,752 patients (and involving 56,759 assessments) over time revealed two patterns:
- The mean scores for pain, nausea, anxiety, and depression remained relatively stable over the 6 months before death.
- Shortness of breath, drowsiness, well-being, lack of appetite, and tiredness increased in severity over time, particularly in the month before death.
In terms of symptoms closer to the EOL, a prospective study documented the symptom profile in the last week of life among 203 cancer patients who died in acute palliative care units.[Level of evidence: II] The proportion of patients able to communicate decreased from 80% to 39% over the last 7 days of life. ESAS anorexia, drowsiness, fatigue, poor well-being, and dyspnea increased in intensity closer to death. In contrast, ESAS depression decreased over time. Dysphagia of solids and liquids and urinary incontinence were also present in an increasing proportion of patients in the last few days of life. Less common but equally troubling symptoms that may occur in the final hours include death rattle and hemorrhage.
The following sections summarize some of the common symptoms and potential approaches to ameliorating those symptoms, based on available evidence. A final note of caution is warranted. Symptoms often cluster, and the presence of a symptom should prompt consideration of other symptoms to avoid inadvertently worsening other symptoms in the cluster. For example, a systematic review of observational studies concluded that there were four common clusters of symptoms (anxiety-depression, nausea-vomiting, nausea-appetite loss, and fatigue-dyspnea-drowsiness-pain).
Terminal delirium occurs before death in 50% to 90% of patients. Most patients have hypoactive delirium, with a decreased level of consciousness. Agitation, hallucinations, and restlessness may occur in a small proportion of patients with hyperactive and/or mixed delirium. Delirium is associated with shorter survival and complicates symptom assessment, communication, and decision making. Furthermore, it can be extremely distressing to caregivers and health professionals.[6-8] Risk factors associated with terminal delirium include hypoxic encephalopathy, metabolic factors, and lack of reversible factors such as psychoactive medications and dehydration. Safety measures include protecting patients from accidents or self-injury while they are restless or agitated. The use of restraints should be minimized. Reorientation strategies are of little use during the final hours of life. Education and support for families witnessing a loved one’s delirium are warranted.
There are no randomized controlled trials on the management of delirium in patients with terminal delirium. (Refer to the PDQ summary on Delirium for a complete review.) Care of the patient with delirium can include stopping unnecessary medications, reversing metabolic abnormalities (if consistent with the goals of care), treating the symptoms of delirium, and providing a safe environment. Agents known to cause delirium include corticosteroids, chemotherapeutic agents, biological response modifiers, opioids, antidepressants, benzodiazepines, and anticholinergic agents. In a small, open-label, prospective trial of 20 cancer patients who developed delirium while being treated with morphine, rotation to fentanyl reduced delirium and improved pain control in 18 patients.[Level of evidence: II]
Onset of effect and nonoral modes of delivery are considered when an agent is being selected to treat delirium at the EOL. Agents that can be used to manage delirium include haloperidol, 1 mg to 4 mg orally, intravenously, or subcutaneously. The dose is usually repeated every 4 to 6 hours but in severe cases can be administered every hour. Chlorpromazine can be used, but intravenous administration can lead to severe hypotension; therefore, it should be used cautiously. Other agents that may be effective include olanzapine, 2.5 mg to 20 mg orally at night (available in an orally disintegrating tablet for patients who cannot swallow);[Level of evidence: II] quetiapine; and risperidone (0.5–2 mg). While no randomized clinical trial demonstrates superiority of any agent over haloperidol, small (underpowered) studies suggest that olanzapine may be comparable to haloperidol. Finally, although benzodiazepines (such as lorazepam) or atypical antipsychotics typically exacerbate delirium, they may be useful in delirium related to alcohol withdrawal and for hyperactive delirium that is not controlled by antipsychotics and other supportive measures. In intractable cases of delirium, palliative sedation may be warranted.
In dying patients, a poorly understood phenomenon that appears to be distinct from delirium is the experience of auditory and/or visual hallucinations that include loved ones who have already died (also known as EOL experience). Although patients may sometimes find these hallucinations comforting, fear of being labeled confused may prevent patients from sharing their experiences with health care professionals. Family members at the bedside may find these hallucinations disconcerting and will require support and reassurance. Consultation with the patient’s or family’s religious or spiritual advisor or the hospital chaplain is often beneficial.
Fatigue is one of the most common symptoms at the EOL and often increases in prevalence and intensity as patients approach the final days of life. Fatigue at the EOL is multidimensional, and its underlying pathophysiology is poorly understood. It may be associated with drowsiness, weakness, and sleep disturbance. Scores on the Palliative Performance Scale also decrease rapidly during the last 7 days of life. No clinical trials have been conducted in patients with only days of life expectancy. Methylphenidate may be useful in selected patients with weeks of life expectancy. (Refer to the PDQ summary on Fatigue for more information.)
Dyspnea, described as shortness of breath or air hunger, is one of the most distressing symptoms for patients and often increases as patients approach the last weeks and days of life.[2,22] The prevalence of dyspnea in adults diagnosed with cancer varies from 21% to 90%, correlated with lung cancer and advanced disease.[Level of evidence: II] Dyspnea may predict shortened survival.
The etiology of dyspnea is usually advanced malignant disease, although other risk factors include ascites, chronic obstructive pulmonary disease, deconditioning, and pneumonia. Dyspnea occurs when more respiratory effort is necessary to overcome obstruction or restrictive disease (e.g., tumor or pleural effusions), when more respiratory muscles are required to maintain adequate breathing (e.g., neuromuscular weakness or cachexia), or when there is an increase in ventilatory need (e.g., hypercapnia or metabolic acidosis). Aggressive interventions such as thoracentesis to treat potentially reversible causes may or may not be appropriate; patients’ prognosis, goals of care, and logistics are first to be taken into account.
In the last days of life, many patients may be confused, making assessment of dyspnea more challenging. Objective measures such as respiratory rate, oxygen saturation, and use of accessory muscles have limited association with patients’ subjective sensation of dyspnea. Caregivers may be able to provide a surrogate response. The Respiratory Distress Observation Scale was developed for patients who could not self-report; however, correlation with patient’s expression of dyspnea was weak to moderate.
The principles and practices for palliation of dyspnea in patients with days of survival are similar to those for patients with longer life expectancies. Opioids, given orally, intravenously, or subcutaneously, are considered to be the first-line option. Patients with evidence of bronchoconstriction may be given bronchodilators.
Corticosteroids may be considered for patients without clear contraindications. Patients with hypoxemia would benefit from supplemental oxygen use. Patients with severe dyspnea and hypoxemic/hypercapnic respiratory failure may require bilevel positive airway pressure and/or high-flow oxygen, which represent noninvasive alternatives to intubation and mechanical ventilation.[28,29] Antibiotics may provide relief from infectious sources of dyspnea; however, the use of these agents should be consistent with a patient’s goals of care. If a patient experiences bronchospasm in conjunction with dyspnea, glucocorticoids or bronchodilators can provide relief. Bronchodilators are used with caution because they can increase anxiety, leading to a worsened sense of dyspnea.
In rare situations, dyspnea may be refractory to all of the treatments described above. In such cases, palliative sedation may be indicated, using benzodiazepines, barbiturates, or neuroleptics. Indeed, refractory dyspnea is the second most common indication for palliative sedation, after agitated delirium. (Refer to the Palliative Sedation section of this summary for more information.)
The prevalence of pain is between 30% and 75% in the last days of life.[18,31] The assessment of pain may be complicated by delirium. Many patients fear uncontrolled pain during the final days of life, but experience suggests that most patients can obtain pain relief and that very high doses of opioids are rarely indicated. Indeed, the average intensity of pain often decreases as patients approach the final days.
Some patients, family members, and health care professionals express concern that opioid use may hasten death. Several studies refute the fear of hastened death associated with opioid use. In several surveys of high-dose opioid use in hospice and palliative care settings, no relationship between opioid dose and survival was found.[32-35]
The principles of pain management remain similar to those for patients earlier in the disease trajectory, with opioids being the standard option. (Refer to the PDQ summary on Pain for a more complete review of parenteral administration of opioids and opioid rotation.) Because consciousness may diminish during this time and swallowing becomes difficult, practitioners need to anticipate alternatives to the oral route. In one study, as patients approached death, the use of intermittent subcutaneous injections and intravenous or subcutaneous infusions increased. Both intravenous and subcutaneous routes are effective in delivering opioids and other agents in the inpatient or home setting. For patients who do not have a preexisting access port or catheter, intermittent or continuous subcutaneous administration provides a painless and effective route of delivery.
Cough is a relatively common symptom in patients with advanced cancer near the EOL. In one small study, 33% of patients with advanced cancer who were enrolled in hospice and who completed the Memorial Symptom Assessment Scale reported cough as a troubling symptom. This compares to a prevalence of lack of energy (68%), pain (63%), and dyspnea (60%). The treatment of troublesome coughing in patients in the final weeks to days of life is largely empiric, although diagnostic imaging or evaluation may occasionally be of value. In another study of patients with advanced cancer admitted to acute palliative care units, the prevalence of cough ranged from 10% to 30% in the last week of life. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information about common causes of cough for which evaluation and targeted intervention may be indicated.) However, simple investigations such as reviewing medications or eliciting a history of symptoms compatible with gastroesophageal reflux disease are warranted because some drugs (e.g., angiotensin-converting enzyme inhibitors) cause cough, or a prescription for antacids may provide relief. In addition, patients may have comorbid conditions that contribute to coughing.
The cough reflex protects the lungs from noxious materials and clears excess secretions. The reflex is initiated by stimulation of peripheral cough receptors, which are transmitted to the brainstem by the vagus nerve. Activation of the central “cough center” mechanism causes a deep inspiration, followed by expiration against a closed glottis; then the glottis opens, allowing expulsion of the air. The empiric approach to cough may be organized as follows:
- Expectorants increase bronchial fluids and reduce the viscosity of secretions, which improves the likelihood of successfully clearing the material. Guaifenesin is commonly available in over-the-counter cold or cough remedies. A reasonable dose is 200 to 400 mg every 4 to 6 hours.
- Antimuscarinics decrease oral secretions, which may initiate a cough reflex if the patient cannot swallow adequately (refer to the Death Rattle section of this summary for more information).
- Centrally acting antitussives suppress the putative cough center in the brain stem. All opioids have antitussive properties. Dextromethorphan is available in over-the-counter cough suppressants. Codeine is commonly prescribed initially; if it is not effective, then patients receive a more potent opioid such as morphine. However, evidence suggests that morphine  or hydrocodone  is preferable.
As discussed in the Dyspnea section of this summary, the use of bronchodilators, corticosteroids, or inhaled steroids is limited to specific indications, given the potential risks and the lack of evidence of benefit outside of specific indications.
The prevalence of constipation ranges from 30% to 50% in the last days of life.[3,31] The use of laxatives for patients who are imminently dying may provide limited benefit. Such patients often have dysphagia and very poor oral intake. Treatment of constipation in patients with only days of expected survival is guided by symptoms. If indicated, laxatives may be given rectally (e.g., bisacodyl and enemas).
Functional dysphagia and structural dysphagia occur in a large proportion of cancer patients in the last days of life. Specifically, patients often experience difficulty swallowing both liquids and solids, which is often associated with anorexia and cachexia. In one study of cancer patients, the oral route of opioid administration was continued in 62% of patients at 4 weeks before death, in 43% at 1 week before death, and in 20% at 24 hours before death. The clinical implication is that essential medications may need to be administered through other routes, such as intravenous, subcutaneous, rectal, and transdermal. Nonessential medications are discontinued.
Supplemental nutrition is of no known benefit and may increase the risk of aspiration and infections. Instead of tube-feeding or ordering nothing by mouth, providing a small amount of food for enjoyment may be reasonable if a patient expresses a desire to eat.
Death rattle, also referred to as excessive secretions, occurs when saliva and other fluids accumulate in the oropharynx and upper airways in a patient who is too weak to clear the throat. Rattle does not appear to be distressing for the patient; however, family members may perceive death rattle as indicating the presence of untreated dyspnea. Thus, the family will benefit from learning about the nature of this symptom and that death rattle is not associated with dyspnea.
Rattle is an indicator of impending death, with an incidence of approximately 50% to 60% in the last days of life and a median onset of 16 to 57 hours before death.[20,42,43] Two types of rattle have been identified:[44,45]
- Real death rattle, or type 1, which is probably caused by salivary secretions.
- Pseudo death rattle, or type 2, which is probably caused by deeper bronchial secretions due to infection, tumor, fluid retention, or aspiration.
In one retrospective chart review, rattle was relieved in more than 90% of patients with salivary secretions, while patients with secretions of pulmonary origin were much less likely to respond to treatment.
The results of clinical trials examining various pharmacologic agents for the treatment of death rattle have so far been negative. A small, double-blind, randomized, controlled trial that compared scopolamine to normal saline found no statistical significance. Another randomized study revealed no difference between atropine and placebo. Results of other randomized controlled studies that examined octreotide, glycopyrrolate, and hyoscine butylbromide  versus scopolamine were also negative.
Despite the lack of clear evidence, pharmacologic therapies are used frequently in clinical practice.[52,53] Among the options described above, glycopyrrolate may be preferred because it is less likely to penetrate the central nervous system, and fewer adverse effects are reported with glycopyrrolate than with other antimuscarinic agents, which could worsen delirium. Glycopyrrolate is available parenterally and in oral tablet form. Doses typically range from 1 mg to 2 mg orally or 0.1 mg to 0.2 mg intravenously or subcutaneously every 4 hours, or by continuous intravenous infusion at a rate of 0.4 mg to 1.2 mg per day. Repositioning may be helpful. Suctioning of excessive secretions may be considered for some patients.
Health care professionals need to monitor patients for opioid-induced neurotoxicity, which could cause myoclonus, hallucinations, and confusion and may mimic terminal delirium. When opioid-induced neurotoxicity is suspected, opioid rotation may be considered. Nonsteroidal anti-inflammatory drugs are often contraindicated in these patients because of the risk of bleeding and renal failure.
Myoclonus is defined as sudden and involuntary movements caused by focal or generalized muscle contractions. The duration of contractions is brief and may be described as shocklike. There are many potential causes of myoclonus, most of which probably stem from the metabolic derangements anticipated as life ends. Medications are an important etiology, especially because many medications may be discontinued. Opioids are probably the most common medication-related cause of myoclonus. The reported prevalence of opioid-induced myoclonus ranges greatly, from 2.7% to 87%.
When opioids are implicated in the development of myoclonus, rotation to a different opioid is the primary treatment. In patients with rapidly impending death, the health care provider may choose to treat the myoclonus rather than make changes in opioids during the final hours. Benzodiazepines, including clonazepam, diazepam, and midazolam, have been recommended.[54-56] The anticonvulsant gabapentin has been reported to be effective in relieving opioid-induced myoclonus, although other reports implicate gabapentin as a cause of myoclonus.[58,59][Level of evidence: III] In one small randomized study, hydration was found to reduce myoclonus.[Level of evidence: I]
There are no reliable data on the frequency of fever. A prospective study of 232 adults with terminal cancer admitted to a hospice and palliative care unit in Taiwan indicated that fever was uncommon and of moderate severity (mean score, 0.37 on a scale of 1–3). There was no increase in fever in the 2 days immediately preceding death. In addition to considering diagnostic evaluation and therapeutic intervention, the clinician needs to carefully assess whether the patient is distressed or negatively affected by the fever.
There are no data showing that fever materially affects the quality of the experience of the dying person. While infection may cause a fever, other etiologies such as medications or the underlying cancer are to be strongly considered. While the main objective in the decision to use antimicrobials is to treat clinically suspected infections in patients who are receiving palliative or hospice care,[62-64][Level of evidence: II] subsequent information suggests that the risks of using empiric antibiotics do not appear justified by the possible benefits for people near death.
Hemorrhage is an uncommon (6%–14%) yet extremely distressing event, especially when it is sudden and catastrophic. Patients with bone marrow failure or liver failure are susceptible to bleeding caused by lack of adequate platelets or coagulation factors; patients with advanced cancer, especially head and neck cancers, experience bleeding caused by fungating wounds or damage to vascular structures from tumor growth, surgery, or radiation. Patients may also experience gastrointestinal bleeding from ulcers, progressive tumor growth, or chemotherapy-induced mucositis.
The management of catastrophic bleeding may include identification of patients who are at risk for catastrophic bleeding and careful communication about risk and potential management strategies. However, two qualitative interview studies of clinicians whose patients experienced catastrophic bleeding at the EOL suggest that it is often impossible to anticipate bleeding and that a proactive approach may cause patients and families undue distress.[67,68] Furthermore, the lack of evidence that catastrophic bleeding can be prevented with medical interventions such as transfusions needs to be taken into account in discussions with patients about the risks of bleeding.
Another strategy is to prepare to administer anxiolytics or sedatives to patients who experience catastrophic bleeding, between the start of the bleeding and death. However, there is little evidence supporting the effectiveness of this approach;[66,68] the experience of clinicians is often that patients become unconscious before the drugs can be administered, and the focus on medications may distract from providing patients and families with reassurance that suffering is unlikely. Nevertheless, the availability of benzodiazepines for rapid sedation of patients who experience catastrophic bleeding may provide some reassurance for family caregivers.
After the death of a patient from a catastrophic hemorrhage, team members are encouraged to verbalize their emotions regarding the experience, and their questions need to be answered.
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