Pain During the Final Hours of Life
Dyspnea
Fatigue
Cough
Death Rattle
Delirium
Fever
Hemorrhage

Symptoms commonly experienced at the end of life include pain, delirium, dyspnea, and rattle. In a study of 200 patients with cancer, noisy breathing or rattle, pain, and urinary dysfunction were the symptoms experienced most frequently during the last 48 hours of life.[1] Other studies confirm that pain, fatigue, cough, delirium, dyspnea, and other symptoms are common in the final days.[2-7] Less common but equally troubling symptoms that may occur in the final hours include fever and hemorrhage.

Many patients fear uncontrolled pain during the final hours of life, while others (including family members and some health care professionals) express concern that opioid use may hasten death. Experience suggests that most patients can obtain pain relief during the final hours of life and that very high doses of opioids are rarely indicated.[8] 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.[9,8,10,11]

Because consciousness may diminish during this time and swallowing becomes difficult, alternatives to the oral route of opioid delivery are indicated. In a study of cancer patients at 4 weeks, 1 week, and 24 hours before death, the oral route of opioid administration was continued in 62%, 43%, and 20% of patients, respectively. As patients approached death, the use of intermittent subcutaneous injections and intravenous or subcutaneous infusions increased.[12] 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 pre-existing access port or catheter, intermittent or continuous subcutaneous administration provides a painless and effective route of delivery.[13] (Refer to the PDQ summary on Pain for a more complete review of parenteral administration of opioids.)

Myoclonic jerking can occur at any time during opioid therapy but is seen more frequently at the end of life. The prevalence of opioid-induced myoclonus ranges greatly, from 2.7% to 87%.[14] Nocturnal myoclonus is common and often precedes opioid-induced myoclonus.[15] The precise cause of opioid-induced myoclonus is unknown; however, several mechanisms have been proposed.[16] High doses of opioids may result in the accumulation of neuroexcitatory metabolites, the best characterized of which are morphine-3-glucuronide and hydromorphone-3-glucouronide.[17,18] Serum and cerebrospinal fluid levels as well as the ratios of these metabolites are elevated in patients who are receiving morphine for cancer and nonmalignant pain and who have myoclonus.[19] This may be particularly true for patients with renal dysfunction, a common phenomenon in the final hours of life.[19,20] However, clinical evidence of myoclonus does not consistently correlate with serum levels of morphine-3-glucuronide.[21] In rodents, hydromorphone-3-glucuronide was more potent in its neuroexcitatory effects, including myoclonus, when compared with morphine-3-glucuronide.[18] Furthermore, other opioids with no known metabolites also have been shown to produce myoclonus.[22] Other opioids, including methadone,[23] meperidine,[24] and transdermal fentanyl,[25] have been implicated in the development of myoclonus.[23]

Very high doses of an opioid may produce myoclonus. One group of investigators reported the development of acute confusion, restlessness, myoclonus, hallucinations, and hyperalgesia due to an inadvertent administration of high-dose intravenous fentanyl.[26] These symptoms were successfully treated with several doses of 0.1 mg to 0.2 mg of intravenous naloxone followed by a continuous infusion of intravenous naloxone (0.2 mg per hour).

Evaluation of the patient with myoclonus includes ruling out other known causes such as surgery to the brain,[27] placement of an intrathecal catheter,[28] AIDS dementia,[29] hypoxia,[30] chlorambucil,[31] metoclopramide,[32] and a rare paraneoplastic syndrome called opsoclonus-myoclonus.[33] The etiology of the paraneoplastic syndrome can also be viral; symptoms include myoclonus, opsoclonus, ataxia, and encephalopathic features.[34] The extent of the work-up to determine the cause of myoclonus varies with the goals of care.

When opioids are implicated in the development of myoclonus, hydration and rotation to other opioids are the primary treatments. There is great variability in individual response to opioids; thus, different agents may be more likely to produce myoclonus or other adverse effects. Because cross-tolerance between opioids is not complete, empirical evidence suggests that after an equianalgesic dose is calculated, that dose should be reduced by approximately 25%, then titrated upward to meet the patient’s analgesic needs.

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. Little research is available regarding the most effective agents for reducing myoclonic jerking. Benzodiazepines, including clonazepam, diazepam, and midazolam, have been recommended.[35,14,36] The mechanism of action of benzodiazepines is through binding to gamma-aminobutyric acid type A receptors within the central nervous system (CNS), leading to CNS depression. At higher doses, benzodiazepines may also limit repetitive neuronal firing, similar to several anticonvulsant compounds such as carbamazepine. The anticonvulsant gabapentin has been reported to be effective in relieving opioid-induced myoclonus,[37] although other reports implicate gabapentin as a cause of myoclonus.[38,39] The antispasmodic baclofen has been used to treat myoclonus due to intraspinal opioid administration.[40] Dantrolene has been used, but it produces significant muscle weakness and hepatotoxicity.[14] In one small randomized study, hydration was found to reduce myoclonus.[41] In cases of severe myoclonus, palliative sedation may be warranted.

Dyspnea, described as shortness of breath or air hunger, is a common symptom in people with cancer during the final days or weeks of life. The prevalence of dyspnea in adults diagnosed with cancer varies from 21% to 90%, correlated with lung cancer and advanced disease.[42] Dyspnea may predict shortened survival. Patients with cancer presenting to an emergency center for treatment of dyspnea had a median overall survival of 12 weeks.[43] Patients with lung cancer had a significantly shorter survival (4 weeks) than did patients with breast cancer (22 weeks). In another study, patients presenting to an emergency department with cancer-related dyspnea who were at greatest risk of imminent death were those with an elevated pulse (100 or more beats per minute) and increased respiratory rate (more than 28 breaths per minute), with a predicted mean survival of less than 2 weeks.[44]

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).[45]

Opioids decrease the perception of air hunger, regardless of the underlying pathophysiology and without causing respiratory depression.[46] This relief is dose related and, experimentally, is reversible by naloxone, an opioid antagonist. Very low doses of opioid, such as morphine 2.5 mg orally, may provide relief in opioid-naïve patients. Higher doses may be indicated in patients who have more intense dyspnea or in patients who are using opioids for pain. As with pain control, gradual upward titration may be needed to provide relief, particularly as symptoms progress.

The use of nebulized opioids for control of dyspnea remains controversial. Nebulized morphine has been administered in the belief that this route would deliver the opioid directly to opioid receptors isolated within the lung.[47] Initial uncontrolled clinical trials and case reports described efficacy using this technique.[48] However, controlled trials have not confirmed these positive results, and as a result, nebulized morphine is generally not indicated.[49] Initial trials of nebulized fentanyl, a lipophilic opioid, suggest efficacy.[25]

Benzodiazepines may be used to treat anxiety commonly associated with dyspnea, but only as an adjunct to opioid therapy. Studies are lacking; however, supplemental oxygen appears to be useful only when hypoxemia is the underlying cause of dyspnea and is not effective in relieving symptoms of dyspnea in people who do not have hypoxemia.[50,51] Alternate strategies include positioning a cool fan toward the patient’s face and repositioning the patient into an upright posture. Cognitive behavioral therapies such as relaxation, breathing control exercises, and psychosocial support may be effective in relieving dyspnea, although patients in the final hours of life may have limited capacity to participate in these techniques.[52] Complementary therapies such as acupuncture and acupressure have been demonstrated to be beneficial for relieving dyspnea, although controlled trials are lacking.[53] Antibiotics may provide relief from infectious sources of dyspnea; however, the use of these agents should be consistent with the patient’s goals of care. If the patient experiences bronchospasm in conjunction with dyspnea, glucocorticoids or bronchodilators can provide relief. Bronchodilators should be 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.

Fatigue at the end of life is multidimensional, and its underlying pathophysiology is poorly understood.[54] Factors that may contribute to fatigue include physical changes, psychological dynamics, and adverse effects associated with the treatment of the disease or associated symptoms. Stimulant medications, along with energy conservation, may be warranted. Refer to the PDQ summary on Fatigue for more information.

In some patients, chronic coughing at the end of life may contribute to suffering.[55] Chronic cough can cause pain, interfere with sleep, aggravate dyspnea, and worsen fatigue. At the end of life, aggressive therapies are not warranted and are more likely to cause increased burden or even harm. Symptom control rather than treatment of the underlying source of the cough is warranted at this time of life. Opioids are strong antitussive agents and are frequently used to suppress cough in this setting. Corticosteroids may shrink swelling associated with lymphangitis. Antibiotics may be used to treat infection and reduce secretions leading to cough. Patients with cancer may have comorbid nonmalignant conditions that can lead to cough. For example, bronchodilators are useful in the management of wheezing and cough associated with chronic obstructive pulmonary disease, and diuretics may be effective in relieving cough due to cardiac failure. Additionally, a review of medications is warranted because some drugs (e.g., ACE inhibitors) can cause cough.

Anecdotal evidence suggests a role for inhaled local anesthetics, which should be utilized judiciously and sparingly; they taste unpleasant and obtund the gag reflex, and anaphylactic reactions to preservatives in these solutions have been documented. In cases of increased sputum production, expectorants and mucolytics have been employed, but the effects have not been well evaluated. Inhaled sodium cromoglycate has shown promise as a safe method of controlling chronic coughing related to lung cancer.[56]

Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.

Rattle, also referred to as death rattle, 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 painful for the patient, but the association of this symptom with impending death often creates fear and anxiety for those at the bedside. Rattle is an indicator of impending death, with an incidence of approximately 50% in people who are actively dying. There is some evidence that the incidence of rattle can be greatly reduced by avoiding the tendency to overhydrate patients at the end of life.[57,58]

In one prospective study of 100 terminally ill cancer patients, rattle began at an average of 57 hours before death.[59] Other studies suggest the median time from onset of rattle to death is much shorter at 16 hours.[60] Two types of rattle have been identified: real death rattle, or type 1, which is probably caused by salivary secretions; and pseudo death rattle, or type 2, which is probably caused by deeper bronchial secretions due to infection, tumor, fluid retention, or aspiration.[61,58] In one retrospective chart review, rattle was relieved in more than 90% of the patients with salivary secretions, while patients with secretions of pulmonary origin were much less likely to respond to treatment.[58]

The pharmacologic treatment of rattle includes antimuscarinic agents, which antagonize acetylcholine (and are thus termed anticholinergic) to reduce secretions.[62] The most commonly used agents include scopolamine, glycopyrrolate, atropine, and hyoscyamine.[57,62] Few data exist to support the use of one agent or route over another. Because most patients are unable to swallow at this time, transdermal or parenteral routes are employed most frequently. Scopolamine, also called l-hyoscine or hyoscine, is available in oral, parenteral, transdermal, and ophthalmic formulations. Some clinicians begin treatment by applying one or two scopolamine transdermal patches behind the ear. Noticeable reduction in secretions usually occurs within 1 or 2 hours after application. If the patch is ineffective, a scopolamine infusion is initiated, with a starting dose of 50 µg per hour intravenously or subcutaneously and titrated upward to 200 µg or more per hour. Adverse effects include CNS depression, although paradoxical excitation has been reported.

Glycopyrrolate (Robinul) is commercially 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. Glycopyrrolate is less likely to penetrate the CNS, and fewer adverse effects are reported than with other antimuscarinic agents, though this is probably of little consequence in the use of glycopyrrolate to relieve rattle at the end of life.

Other drugs that can assist with reducing secretions are atropine and hyoscyamine.[57,62] Doses for these agents are included in the table on Common Symptoms at End of Life and Their Treatment. In addition to these agents, diuretics such as furosemide can sometimes eliminate excess fluids that build up in the upper airways. Reducing parenteral fluids can help reduce excess secretions. None of these measures appear to be effective when the underlying cause of rattle is deep fluid accumulation, such as occurs with pneumonia.[63]

Nonpharmacologic interventions include repositioning the patient by elevating the head of the bed or turning the patient to either side. Reducing or eliminating additional fluids and feedings alleviates additional fluid accumulation in the body. Family members may request suctioning, but this can be traumatic and cause bleeding or stimulate the gag reflex. If truly indicated, suctioning should not be done beyond the oral cavity.

Delirium is common during the final days of life.[4,64] There are two general presentations of delirium: hyperactive and hypoactive. (Refer to the PDQ summary on Cognitive Disorders and Delirium for a complete review.) The hyperactive form of delirium includes agitation, hallucinations, and restlessness.[65] In hypoactive delirium, the patient is withdrawn and quiet; as a result, this form of delirium may be underdiagnosed.[66,64] Although the etiology of either form of delirium is poorly understood, metabolic changes (e.g., hypercalcemia, hypoglycemia, opioid metabolites), dehydration, and drug interactions are implicated.[66-68] Other potential causes of delirium include cancer within the CNS, a full bladder, fecal impaction, dyspnea, or withdrawal from alcohol or benzodiazepines.

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.[68] To limit the potential for drug interactions, medications that are no longer useful or that are inconsistent with the goals of care should be stopped. For example, cholesterol-lowering agents are rarely beneficial at this time of life, but many patients admitted to hospice remain on these medications.

Onset of effect and nonoral modes of delivery should be considered when an agent is being selected to treat delirium at the end of life. Agents that can relieve delirium relatively quickly include haloperidol, 1 mg to 4 mg orally, intravenously, or subcutaneously.[69] The dose is usually repeated every 6 hours but in severe cases can be administered every hour. 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).[70] 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. Chlorpromazine can be used, but intravenous administration can lead to severe hypotension; therefore, it should be used cautiously.[71] In intractable cases of delirium, palliative sedation may be warranted. Safety measures include protecting patients from accidents or self-injury while they are restless or agitated. The use of restraints is controversial; other strategies include having family members or sitters at the bedside to prevent harm. 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; one survey of family members found high levels of distress caused by observing delirium.[72]

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. Although patients may sometimes find these hallucinations comforting, fear of being labeled confused may prevent patients from sharing their experiences with health care professionals.[73] Family members at the bedside may find these hallucinations disconcerting and will require support and reassurance. Consultation with the patient’s or family’s minister, rabbi, priest, or imam; the hospital chaplain; or other spiritual advisor is often beneficial.

Terminally ill patients experience a high incidence of fever and infections.[74,75] A number of retrospective studies have shown that a large number of patients who are receiving hospice or palliative care are treated with antibiotics for suspected or documented infections.[76-79]

The benefits and burdens of the use of antimicrobials in this patient population are topics of much discussion.[76,77,79,80] Three prospective studies have suggested that symptom control may be the main objective in the decision to use antimicrobials to treat clinically suspected or documented infections in patients who are receiving palliative or hospice care.[81-83]

Difficulties in treating symptoms include predicting which patients will obtain symptom relief and which patients will experience only the additional burdens of treatment. Determining the cause of fever (e.g., infection, tumor, or another cause) and deciding which symptoms from suspected infections might respond to various antimicrobial interventions can be difficult clinical judgments, particularly in patients who have multiple active medical problems and for whom the goal of treatment is symptom control.

Hemorrhage is an uncommon (6%–10%) yet extremely disturbing symptom that can arise from cancer or its treatment.[32,84,85] Patients at particular risk include those with head and neck cancers with tumor infiltration into the carotid artery.[85] Radiation therapy to this region can result in thinning of the walls of the vessels, increasing the risk of bleeding. Slow leakage of blood from eroded areas can signal risk of hemorrhage; however, early signs are frequently not apparent, and bleeding can occur without warning. Other cancers that can lead to sudden hemorrhage include gastric or esophageal cancers that perforate, leading to a rapidly fatal upper gastrointestinal bleed.[32,84] Leukemias and other hematologic disorders place patients at risk for hemorrhage. Disseminated intravascular coagulopathy, idiopathic thrombocytopenia, or other platelet abnormalities can lead to sudden hemorrhage.

When chronic bleeding occurs, management may include hemostatic dressings or agents, radiation therapy, endoscopy, arterial embolization, or surgery may be warranted. Systemic interventions include the use of vitamin K or blood products. However, the goals of care are comfort oriented when catastrophic hemorrhage occurs at the end of life. Optimally, code status has already been discussed; resuscitation is rarely effective. Supportive care is critical, for both the patient and family members at the bedside. Although survival after hemorrhage is very limited (usually a few minutes), patients may be initially aware of events around them. Fast-acting agents such as midazolam may sedate the patient during this distressing event.[86]

The following steps should be taken when bleeding occurs:

• Cover the area with dark-colored (e.g., blue or green) towels to limit visual exposure to the blood.



• Speak calmly and reassure the patient that he or she is not alone (and, if loved ones are in attendance, let the patient know they are there).



• Clean the area rapidly because blood can produce a foul odor that may be distressing to loved ones.



• Provide support to family members.

Oncology, palliative care, and other units that care for patients at risk for hemorrhage should have supplies (towels, sedatives) and standing orders in place for rapid employment. Support is essential for all members of the health care team, including novice clinicians or nonclinical staff who might be in attendance, such as chaplains or social workers. Team members should be encouraged to verbalize their emotions regarding the experience, and their questions should be answered.

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