Which characteristic is a typical symptom that the dying person experiences shortly before death?

The Final Days to Weeks of Life

Providing excellent care toward the end of life [EOL] requires an ability to anticipate when to focus mainly on palliation of symptoms and quality of life instead of disease treatment.[1] Prognostic information plays an important role for making treatment decisions and planning for the EOL. However, the available literature suggests that medical providers inaccurately predict how long patients will live and tend to overestimate survival times.[2,3] This appears to hold true even for providers who are experienced in treating patients who are terminally ill. In a multicenter cohort study of 230 hospitalized patients with advanced cancer, palliative care providers correctly predicted time to death for only 41% of patients. Survival time was overestimated in 85% of patients for whom medical providers gave inaccurate predictions, and providers were particularly likely to overestimate survival for Black and Latino patients.[4]

Providers attempting to make prognostic determinations may attend to symptoms that may herald the EOL, or they may observe trends in patients’ functional status. For more information, see the Impending Death section.

For example, one group of investigators [5] retrospectively analyzed nearly 71,000 Palliative Performance Scale [PPS] scores obtained from a cohort of 11,374 adult outpatients with cancer who were assessed by physicians or nurses at the time of clinic visits. The PPS is an 11-point scale describing a patient’s level of ambulation, level of activity, evidence of disease, ability to perform self-care, nutritional intake, and level of consciousness.

The investigators assigned patients to one of four states:

• Stable [PPS score, 70–100].
• Transitional [PPS score, 40–60].
• EOL [PPS score, 10–30].
• Dead.

Of the 4,806 patients who died during the study period, 49% were recorded as being in the transitional state, and 46% were recorded as being in the stable state. For a patient who was in the transitional state, the probability of dying within a month was 24.1%, which was less than that for a patient in the EOL state [73.5%]. The results suggest that serial measurement of the PPS may aid patients and clinicians in identifying the approach of the EOL.

In contrast to the data indicating that clinicians are relatively poor independent prognosticators, a study published in 2019 compared the relative accuracies of the PPS, the Palliative Prognostic Index, and the Palliative Prognostic Score with clinicians' predictions of survival for patients with advanced cancer who were admitted to an inpatient palliative care unit. At study enrollment, the investigators calculated the scores from the three prognostication tools for 204 patients and asked the unit’s palliative care attending physician to estimate each patient’s life expectancy [0–14 days, 15–42 days, or over 42 days]. Reasons for admission included pain [90.7%], bowel obstruction [48.0%], delirium [36.3%], dyspnea [34.8%], weakness [27.9%], and nausea [23.5%].[6]

The study found that all four prognostic measures had similar levels of accuracy, with the exception of clinician predictions of survival, which were more accurate for 7-day survival. The authors hypothesized that clinician predictions of survival may be comparable or superior to prognostication tools for patients with shorter prognoses [days to weeks of survival] and may become less accurate for patients who live for months or longer.[6] However, clinician predictions of survival may have been unusually accurate in this study because of the evaluators’ subspecialty experience in palliative care and the more predictable environment and patient population of an acute palliative care unit.

Impending Death

Impending death, or actively dying, refers to the process in which patients who are expected to die within 3 days exhibit a constellation of symptoms.[7] In the final days of life, patients often experience progressive decline in their neurocognitive, cardiovascular, respiratory, gastrointestinal, genitourinary, and muscular function, which is characteristic of the dying process. A number of highly specific clinical signs can be used to help clinicians establish the diagnosis of impending death [i.e., death within days].[8,9]

Impending death is a diagnostic issue rather than a prognostic phenomenon because it is an irreversible physiological process. The ability to diagnose impending death with confidence is of utmost importance to clinicians because it could affect their communication with patients and families and inform complex health care decisions such as:[10,11]

• Hospital discharge.
• Discontinuation of prescription medications.
• Artificial nutrition.
• Use of life support measures.
• Enrollment on clinical care pathways.

Because clinicians often overestimate survival,[2,3] they often hesitate to diagnose impending death without adequate supporting evidence.

One study examined five signs in cancer patients recognized as actively dying. Investigators reported that the median time to death from the onset of death rattle was 23 hours; from the onset of respiration with mandibular movement, 2.5 hours; from the onset of cyanosis in extremities, 1 hour; and from the onset of pulselessness on the radial artery, 2.6 hours.[12]

The Investigating the Process of Dying study systematically examined physical signs in 357 consecutive cancer patients.[9] Among the ten target physical signs, there were three early signs and seven late signs. The early signs had high frequency, occurred more than 1 week before death, and had moderate predictive value that a patient would die in 3 days. Early signs included the following:

• Decreased level of consciousness [Richmond Agitation-Sedation Scale score of –2 or lower].
• Decreased performance status [PPS score ≤20%].
• Dysphagia of liquids.

The late signs occurred mostly in the last 3 days of life, had lower frequency, and were highly specific for impending death in 3 days. Late signs included the following:[9]

• Pulselessness on the radial artery.
• Respiration with mandibular movement.
• Decreased urine output.
• Cheyne-Stokes breathing.
• Death rattle.
• Apnea periods.
• Peripheral cyanosis.

In particular, the high positive likelihood ratios [LRs] of pulselessness on the radial artery [positive LR, 15.6], respiration with mandibular movement [positive LR, 10], decreased urine output [≤200 cc/d] [positive LR, 15.2], Cheyne-Stokes breathing [positive LR, 12.4], and death rattle [positive LR, 9] suggest that these physical signs can be useful for the diagnosis of impending death.[9] Because of low sensitivity, the absence of these signs cannot rule out impending death. A prospective observational study that examined vital signs in the last 7 days of life reported that blood pressure and oxygen saturation decreased as death approached. However, a large proportion of patients had normal vital signs, even in the last 12 hours of life. Moderate changes in vital signs from baseline could not definitively rule in or rule out impending death in 3 days. Therefore, predicting death is difficult, even with careful and repeated observations.[13]

Several other late signs that have been found to be useful for the diagnosis of impending death include the following:[14]

• Nonreactive pupils [positive LR, 16.7; 95% confidence interval [CI], 14.9–18.6].
• Decreased response to verbal stimuli [positive LR, 8.3; 95% CI, 7.7–9].
• Decreased response to visual stimuli [positive LR, 6.7; 95% CI, 6.3–7.1].
• Inability to close eyelids [positive LR, 13.6; 95% CI, 11.7–15.5].
• Drooping of the nasolabial fold [positive LR, 8.3; 95% CI, 7.7–8.9].
• Hyperextension of the neck [positive LR, 7.3; 95% CI, 6.7–8].
• Grunting of vocal cords [positive LR, 11.8; 95% CI, 10.3–13.4].
• Upper gastrointestinal bleeding [positive LR, 10.3; 95% CI, 9.5–11.1].

In conclusion, bedside physical signs may be useful in helping clinicians diagnose impending death with greater confidence, which can, in turn, assist in clinical decision making and communication with families.

Care During the Final Hours of Life

The recognition of impending death is also an opportunity to encourage family members to notify individuals close to the patient who may want an opportunity to “say goodbye.” In the final hours of life, care should be directed toward the patient and the patient’s loved ones. In addition to continuing a careful and thoughtful approach to any symptoms a patient is experiencing, preparing family and friends for a patient’s death is critical. Preparations include the following:

• Acknowledging the symptoms that are likely to occur.
• Articulating a plan to respond to the symptoms.
• Eliciting fears or concerns of family members.
• Assuring that respectfully allowing life to end is appropriate at this point in the patient’s life.

For more information, see the Symptoms During the Final Months, Weeks, and Days of Life section.

Encouraging family members who desire to “do something” to participate in the care of the patient [e.g., moistening the mouth] may be helpful. In the final days to hours of life, patients often have limited, transitory moments of lucidity. Family members should be prepared for this and educated that this is a natural aspect of the dying process and not necessarily a result of medications being administered for symptoms or a sign that the patient is doing better than predicted. Despite their limited ability to interact, patients may be aware of the presence of others; thus, loved ones can be encouraged to speak to the patient as if he or she can hear them.

Educating family members about certain signs is critical. In the final hours of life, patients often experience a decreased desire to eat or drink, as evidenced by clenched teeth or turning from offered food and fluids. This behavior may be difficult for family members to accept because of the meaning of food in our society and the inference that the patient is “starving.” Family members should be advised that forcing food or fluids can lead to aspiration. Reframing will include teaching the family to provide ice chips or a moistened oral applicator to keep a patient’s mouth and lips moist. Finally, the death rattle is particularly distressing to family members. It is important to assure family members that death rattle is a natural phenomenon and to pay careful attention to repositioning the patient and explain why tracheal suctioning is not warranted.[15] For more information, see the Death Rattle section.

For patients who die in the hospital, clinicians need to be prepared to inquire about the family’s desire for an autopsy, offering reassurance that the body will be treated with respect and that open-casket services are still possible, if desired.

Health care professionals, preferably in consultation with a chaplain or religious leader designated by the patient and/or family, need to explore with families any fears associated with the time of death and any cultural or religious rituals that may be important to them. Such rituals might include placement of the body [e.g., the head of the bed facing Mecca for an Islamic patient] or having only same-sex caregivers or family members wash the body [as practiced in many orthodox religions]. When death occurs, expressions of grief by those at the bedside vary greatly, dictated in part by culture and in part by their preparation for the death. Chaplains are to be consulted as early as possible if the family accepts this assistance. Health care providers can offer to assist families in contacting loved ones and making other arrangements, including contacting a funeral home. For more information, see Spirituality in Cancer Care.

Overview

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:[1]

• 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.[2] 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 the following nine symptoms:

• Anxiety.
• Lack of appetite.
• Depression.
• Drowsiness.
• Nausea.
• Pain.
• Shortness of breath.
• Tiredness.
• 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:[2]

• 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.[3][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].[4]

Delirium

Terminal delirium occurs before death in 50% to 90% of patients.[5] 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 the following:[9]

• Hypoxic encephalopathy.
• Metabolic factors.
• 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 few randomized controlled trials on the management of delirium in patients with terminal or irreversible delirium.[10] 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.
• 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.[11][Level of evidence: II]

The onset of effect and non-oral 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 [IV], or subcutaneously.[12] The dose is usually repeated every 4 to 6 hours but in severe cases can be administered every hour. Chlorpromazine can be used, but IV administration can lead to severe hypotension; therefore, it should be used cautiously.[13] 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];[14][Level of evidence: II] quetiapine;[15] and risperidone [0.5–2 mg].[16] While no randomized clinical trial demonstrates superiority of any agent over haloperidol, small [underpowered] studies suggest that olanzapine may be comparable to haloperidol.

In addition, a small, double-blind, randomized trial at the University of Texas MD Anderson Cancer Center compared the relative sedating effects of scheduled haloperidol, chlorpromazine, and a combination of the two for advanced-cancer patients with agitated delirium.[17] The investigators screened 998 patients from the palliative and supportive care unit and randomly assigned 68 patients who met the inclusion criteria for having agitated delirium refractory to scheduled haloperidol 1 to 8 mg/day to three intervention groups: haloperidol 2 mg every 4 hours, chlorpromazine 25 mg every 4 hours, or haloperidol 1 mg combined with chlorpromazine 12.5 mg every 4 hours. Rescue doses equivalent to the standing dose were allowed every 1 hour as needed and once at protocol initiation, with the goal of producing sedation with a Richmond Agitation-Sedation Scale [RASS] score of 0 to –2. Dose escalations and rescue doses were allowed for persistent symptoms.

Of the 68 randomized patients, 45 patients were treated and monitored until death or discharge. Patients in all three groups demonstrated clinically significant decreases in RASS scores within 30 minutes and remained sedated at 24 hours. No statistically significant difference in sedation levels was observed between the three protocols. However, the chlorpromazine group was less likely to develop breakthrough restlessness requiring rescue doses or baseline dosing increases. The most common adverse event was hypotension, which was seen in 40% of patients in the haloperidol group, 31% of those in the chlorpromazine group, and 21% of those in the combination group.[17] One patient in the combination group discontinued therapy because of akathisia. The study was limited by a small sample size and the lack of a placebo group. Although all three interventions were effective at controlling agitation, it is worth noting that they controlled agitation via significant sedation, which may not be desired by all patients and/or their families.

Although benzodiazepines [such as lorazepam] or antidopaminergic medications could exacerbate delirium, they may be useful for the treatment of hyperactive delirium that is not controlled by other supportive measures. In intractable cases of delirium, palliative sedation may be warranted. A randomized controlled trial compared the effect of lorazepam versus placebo as an adjunctive to haloperidol on the intensity of agitation in 58 patients with delirium in a palliative care unit.[18] Patients were eligible for the study if they had a diagnosis of delirium with a history of agitation [hyperactive delirium subtype]. Once enrolled, patients began a regimen of haloperidol 2 mg IV every 4 hours, with 2 mg IV hourly as needed for agitation. The RASS score was monitored every 2 hours until the score was 2 or higher. At this threshold, the patient received lorazepam 3 mg or matching placebo with one additional dose of haloperidol 2 mg. The primary outcome of RASS score reduction was measured 8 hours after administration of the study drug. Patients in the lorazepam group experienced a statistically significant reduction in RASS score [increased sedation] at 8 hours [–4.1 points for lorazepam/haloperidol vs. –2.3 points for placebo/haloperidol; mean difference, –1.9 points [95% confidence interval, –2.8 to –0.9]; P < .001]. Lorazepam-treated patients also required significantly lower doses of rescue neuroleptics and, after receiving the study medication, were perceived to be in greater comfort by caregivers and nurses. No differences in mortality were noted between the treatment arms.

Caution should be exercised in the use of this protocol because of the increased risk of significant sedation. The reduction in agitation is directly proportional to increased sedation to the point of patients being “minimally responsive to verbal stimulus” or conversion to hypoactive delirium during the remaining hours of life.[19] Communication with patients and surrogates to determine goal-concordant care in the setting of terminal or hyperactive delirium is imperative to ensure that sedation is an intended outcome of this protocol in which symptom reduction is the primary intention of the intervention. Intensive evaluation of RASS scores may be challenging for the bedside nurse. Finally, this study examined a single dose of lorazepam 3 mg; repeat doses were not studied and may accumulate in patients with liver and/or renal dysfunction.[18]

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.[20] 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

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.[21] Fatigue at the EOL is multidimensional, and its underlying pathophysiology is poorly understood.[22] 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.[23] 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.[24] For more information, see Fatigue.

Dyspnea

Treatment options for dyspnea, defined as difficult, painful breathing or shortness of breath, include opioids, nasal cannula oxygen, fans, raising the head of the bed, noninvasive ventilation, and adjunctive agents.

Pain

The prevalence of pain is between 30% and 75% in the last days of life.[21,29] 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.[30] Indeed, the average intensity of pain often decreases as patients approach the final days.[2]

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.[30-33]

The principles of pain management remain similar to those for patients earlier in the disease trajectory, with opioids being the standard option. 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 IV or subcutaneous infusions increased.[34] Both IV 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.[35] For a more complete review of parenteral administration of opioids and opioid rotation, see Cancer Pain.

Cough

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.[36] 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.[3] 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. For more information about common causes of cough for which evaluation and targeted intervention may be indicated, see Cardiopulmonary Syndromes.

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.[37] 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. For more information, see the Death Rattle section.
• 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 [38] or hydrocodone [39] is preferable.

As discussed in the Dyspnea section, 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.

Constipation

The prevalence of constipation ranges from 30% to 50% in the last days of life.[3,29] 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 or enemas].

Dysphagia

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.[34] The clinical implication is that essential medications may need to be administered through other routes, such as IV, subcutaneous, rectal, and transdermal. Nonessential medications are discontinued.

Artificial nutrition is of no known benefit at the EOL and may increase the risk of aspiration and/or 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. For more information, see the sections on Artificial Hydration and Artificial Nutrition.

Death Rattle

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.[23,40,41] Two types of rattle have been identified:[42,43]

• 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.[43]

The results of clinical trials examining various pharmacological agents for the treatment of death rattle have so far been negative.[44] A small, double-blind, randomized, controlled trial that compared scopolamine to normal saline found no statistical significance.[45] Another randomized study revealed no difference between atropine and placebo.[46] Results of other randomized controlled studies that examined octreotide,[47] glycopyrrolate,[48] and hyoscine butylbromide [49] versus scopolamine were also negative.

Despite the lack of clear evidence, pharmacological therapies are used frequently in clinical practice.[50,51] Among the options described above, glycopyrrolate may be preferred because it is less likely to penetrate the central nervous system and has fewer adverse effects than other antimuscarinic agents, which can 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 IV or subcutaneously every 4 hours, or by continuous IV infusion at a rate of 0.4 mg to 1.2 mg per day. Repositioning is often helpful. Suctioning of excessive secretions may be considered for some patients, although this may elicit the gag reflex and be counterproductive.

Given the limited efficacy of pharmacological interventions for death rattle, clinicians should consider factors that can help prevent it. In one secondary analysis of an observational study of patients who were dying of abdominal malignancies, audible death rattle was correlated with the volume of IV hydration administered. Patients who received more than 500 mL of IV fluid in the week before death had a significantly higher risk of developing death rattle in the 48 hours before death than patients who received less than 500 mL of IV fluid. Along with patient wishes and concomitant symptoms, clinicians should consider limiting IV hydration in the final days before death.[52][Level of evidence: II] For more information, see the Artificial Hydration section.

Opioid-Induced Neurotoxicity and Myoclonus

Health care professionals need to monitor patients for opioid-induced neurotoxicity, which can cause symptoms such as myoclonus, hallucinations, hyperalgesia, seizures, and confusion, and which may mimic terminal delirium. One retrospective study examined 390 patients with advanced cancer at the University of Texas MD Anderson Cancer Center who had been taking opioids for 24 hours or longer and who received palliative care consultations. The study suggested that 15% of these patients developed at least one symptom of opioid-induced neurotoxicity, the most common of which was delirium [47%].[53] When opioid-induced neurotoxicity is suspected, opioid rotation may be considered.[11]

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, particularly opioids, are another potential etiology. The reported prevalence of opioid-induced myoclonus ranges greatly, from 2.7% to 87%.[54]

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,[57] 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.[60][Level of evidence: I]

Fever

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].[61] 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.[65]

Catastrophic Hemorrhage

Hemorrhage is an uncommon [6%–14%] yet extremely distressing event, especially when it is sudden and catastrophic.[66] 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 of 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. Additionally, having dark towels available to camouflage the blood can reduce distress experienced by loved ones who are present at the time of hemorrhage.

After the death of a patient from a catastrophic hemorrhage, family members and team members are encouraged to verbalize their emotions regarding the experience, and their questions need to be answered.

Palliative Sedation to Treat EOL Symptoms

In rare situations, EOL symptoms may be refractory to all of the treatments described above. In such cases, palliative sedation may be indicated, using benzodiazepines, barbiturates, or neuroleptics. Refractory dyspnea is the second most common indication for palliative sedation, after agitated delirium.[69] For more information, see the Palliative Sedation section.

The Decision to Discontinue Disease-Directed Therapies

The Decision to Enroll in Hospice

Patients with advanced cancer who receive hospice care appear to experience better psychological adjustment, fewer burdensome symptoms, increased satisfaction, improved communication, and better deaths without hastening death.[16-19] The rate of hospice enrollment for people with cancer has increased in recent years; however, this increase is tempered by a reduction in the average length of hospice stay. Because of the association of longer hospice stays with caregivers’ perceptions of improved quality of care and increased satisfaction with care, the latter finding is especially concerning.[20,21]

Multiple patient demographic factors [e.g., younger age, married status, female gender, White race, greater affluence, and geographic region] are associated with increased hospice enrollment. In one study, however, physician characteristics were more important than patient characteristics in determining hospice enrollment.[22] This may reflect the observation that patients concede more control to oncologists over time, especially if treatment decisions involve noncurative chemotherapy for metastatic cancer.[23]

There are many potential barriers to timely hospice enrollment. Forgoing disease-directed therapy is one of the barriers cited by patients, caregivers, physicians, and hospice services. The Medicare Care Choices Model, a novel Centers for Medicare & Medicaid Services [CMS] pilot program, is evaluating a new supportive care model that allows beneficiaries to receive supportive care from selected hospice providers, alongside therapy directed toward their terminal condition. This 5-year project enrolled its first cohort of patients in January 2016 and the second cohort in January 2018. CMS will evaluate whether providing these supportive services can improve patient quality of life and care, improve patient and family satisfaction, and inform a new payment system for the Medicare and Medicaid programs.

The purpose of this section is to provide the oncology clinician with insights into the decision to enroll in hospice, and to encourage a full discussion of hospice as an important EOL option for patients with advanced cancer. The related study [24] provides potential strategies to address some of the patient-level barriers.

Barriers are summarized in the following subsections on the basis of whether they arise predominantly from the perspective of the patient, caregiver, physician, or hospice, including eligibility criteria for enrollment.

Choosing the Desired Place of Death