80PART 1 The Profession of Medicine

Constipation • FREQUENCY Constipation is reported in up to

70–100% of patients requiring palliative care.

ETIOLOGY Although hypercalcemia and other factors can cause constipation, it is most frequently a predictable consequence of the use of

opioids for pain and dyspnea relief and of the anticholinergic effects of

tricyclic antidepressants, as well as due to the inactivity and poor diets

common among seriously ill patients. If left untreated, constipation can

cause substantial pain and vomiting and also is associated with confusion and delirium. Whenever opioids and other medications known

to cause constipation are used, preemptive treatment for constipation

should be instituted.

ASSESSMENT Assessing constipation can be difficult because people

describe it differently. Four commonly used assessment scales are the

Bristol Stool Form Scale, the Constipation Assessment Scale, the Constipation Visual Analogue Scale, and the Eton Scale Risk Assessment

for Constipation. The Bowel Function Index can be used to quantify opioid-induced constipation. The physician should establish the

patient’s previous bowel habits, as well as any changes in subjective and

objective qualities such as bloating or decreased frequency. Abdominal

and rectal examinations should be performed to exclude impaction

or an acute abdomen. Radiographic assessments beyond a simple flat

plate of the abdomen in cases in which obstruction is suspected are

rarely necessary.

INTERVENTION Any measure to address constipation during end-oflife care should include interventions to reestablish comfortable bowel

habits and to relieve pain or discomfort. Although physical activity,

adequate hydration, and dietary treatments with fiber can be helpful, each is limited in its effectiveness for most seriously ill patients,

and fiber may exacerbate problems in the setting of dehydration or

if impaired motility is the etiology. Fiber is contraindicated in the

presence of opioid use. Stimulant and osmotic laxatives, stool softeners, fluids, and enemas are the mainstays of therapy (Table 12-5). To

prevent constipation from opioids and other medications, a combination of a laxative and a stool softener (such as senna and docusate)

should be used. If after several days of treatment a bowel movement

has not occurred, a rectal examination to remove impacted stool and

place a suppository is necessary. For patients with impending bowel

TABLE 12-5 Medications for the Management of Constipation

INTERVENTION DOSE COMMENT

Stimulant laxatives These agents directly stimulate

peristalsis and may reduce

colonic absorption of water.

Prune juice 120–240 mL/d Work in 6–12 h.

Senna (Senokot) 2–8 tablets PO bid

Bisacodyl 5–15 mg/d PO, PR

Osmotic laxatives These agents are not absorbed.

They attract and retain water in

the gastrointestinal tract.

Lactulose 15–30 mL PO

q4–8h

Lactulose may cause flatulence

and bloating.

 Magnesium hydroxide

(Milk of Magnesia)

15–30 mL/d PO Lactulose works in 1 day,

magnesium products in 6 h.

Magnesium citrate 125–250 mL/d PO

Stool softeners These agents work by

increasing water secretion and

as detergents, increasing water

penetration into the stool.

 Sodium docusate

(Colace)

300–600 mg/d PO Work in 1–3 days.

Calcium docusate 300–600 mg/d PO

Suppositories and

enemas

Bisacodyl 10–15 PR qd

 Sodium phosphate

enema

PR qd Fixed dose, 4.5 oz, Fleet’s.

obstruction or gastric stasis, octreotide to reduce secretions can be

helpful. For patients in whom the suspected mechanism is dysmotility,

metoclopramide can be helpful.

Nausea • FREQUENCY Up to 70% of patients with advanced cancer

have nausea, defined as the subjective sensation of wanting to vomit.

ETIOLOGY Nausea and vomiting are both caused by stimulation at

one of four sites: the GI tract, the vestibular system, the chemoreceptor

trigger zone (CTZ), and the cerebral cortex. Medical treatments for

nausea are aimed at receptors at each of these sites: the GI tract contains mechanoreceptors, chemoreceptors, and 5-hydroxytryptamine

type 3 (5-HT3

) receptors; the vestibular system probably contains histamine and acetylcholine receptors; and the CTZ contains chemoreceptors, dopamine type 2 receptors, and 5-HT3 receptors. An example of

nausea that most likely is mediated by the cortex is anticipatory nausea

before a dose of chemotherapy or other noxious stimuli.

Specific causes of nausea include metabolic changes (liver failure,

uremia from renal failure, hypercalcemia), bowel obstruction, constipation, infection, GERD, vestibular disease, brain metastases, medications (including antibiotics, NSAIDs, proton pump inhibitors, opioids,

and chemotherapy), and radiation therapy. Anxiety can also contribute

to nausea.

INTERVENTION Medical treatment of nausea is directed at the anatomic and receptor-mediated cause revealed by a careful history and

physical examination. When no specific cause of nausea is identified,

many advocate beginning treatment with metoclopramide; a serotonin

type 3 (5-HT3

) receptor antagonist such as ondansetron, granisetron,

palonosetron, dolasetron, tropisetron, or ramosetron; or a dopamine

antagonist such as chlorpromazine, haloperidol, or prochlorperazine.

When decreased motility is suspected, metoclopramide can be an

effective treatment. When inflammation of the GI tract is suspected,

glucocorticoids, such as dexamethasone, are an appropriate treatment.

For nausea that follows chemotherapy and radiation therapy, one of the

5-HT3

 receptor antagonists or neurokinin-1 antagonists, such as aprepitant or fosaprepitant, is recommended. Clinicians should attempt

prevention of postchemotherapy nausea, rather than simply providing

treatment after the fact. Current clinical guidelines recommend tailoring the strength of treatments to the specific emetic risk posed by a

specific chemotherapy drug. When a vestibular cause (such as “motion

sickness” or labyrinthitis) is suspected, antihistamines, such as meclizine (whose primary side effect is drowsiness), or anticholinergics, such

as scopolamine, can be effective. In anticipatory nausea, patients can

benefit from nonpharmacologic interventions, such as biofeedback

and hypnosis. The most common pharmacologic intervention for

anticipatory nausea is a benzodiazepine, such as lorazepam. As with

antihistamines, drowsiness and confusion are the main side effects.

The use of medical marijuana or oral cannabinoids for palliative

treatment of nausea is controversial, as there are no controlled trials showing its effectiveness for patients at the end of life. A 2015

meta-analysis showed “low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting

due to chemotherapy,” and such treatments are not as good as 5-HT3

receptor antagonists and can sometimes even cause cannabis hyperemesis syndrome. Older patients, who compose the vast majority of

dying patients, seem to tolerate cannabinoids poorly.

Dyspnea • FREQUENCY Dyspnea is the subjective experience of

being short of breath. Over 50%, and as many as 75%, of dying patients,

especially those with lung cancer, metastases to the lung, CHF, and

COPD, experience dyspnea at some point near the end of life. Dyspnea

is among the most distressing of physical symptoms and can be even

more distressing than pain.

ASSESSMENT As with pain, dyspnea is a subjective experience that

may not correlate with objective measures of PO2

, PCO2

, or respiratory rate. Consequently, measurements of oxygen saturation through

pulse oximetry or blood gases are rarely helpful in guiding therapy.

Despite the limitations of existing assessment methods, physicians

should regularly assess and document patients’ experience of dyspnea

Palliative and End-of-Life Care

81CHAPTER 12

TABLE 12-6 Medications for the Management of Dyspnea

INTERVENTION DOSE COMMENTS

Weak opioids For patients with mild dyspnea

 Codeine (or codeine

with 325 mg

acetaminophen)

30 mg PO q4h For opioid-naïve patients

Hydrocodone 5 mg PO q4h

Strong opioids For opioid-naïve patients with

moderate to severe dyspnea

Morphine 5–10 mg PO q4h For patients already taking

opioids for pain or other

symptoms

30–50% of baseline

opioid dose q4h

Oxycodone 5–10 mg PO q4h

Hydromorphone 1–2 mg PO q4h

Anxiolytics Give a dose every hour until the

patient is relaxed; then provide

a dose for maintenance

Lorazepam 0.5–2.0 mg PO/SL/IV

qh then q4–6h

Clonazepam 0.25–2.0 mg PO q12h

Midazolam 0.5 mg IV q15min

Fatigue • FREQUENCY Fatigue is one of the most commonly

reported symptoms not only of cancer treatment but also of the palliative care of multiple sclerosis, COPD, heart failure, and HIV. More

than 90% of terminally ill patients experience fatigue and/or weakness.

Fatigue is frequently cited as one of the most distressing symptoms in

these patients.

ETIOLOGY The multiple causes of fatigue in the terminally ill can be

categorized as resulting from the underlying disease; from diseaseinduced factors such as tumor necrosis factor and other cytokines; and

from secondary factors such as dehydration, anemia, infection, hypothyroidism, and drug side effects. In addition to low caloric intake, loss

of muscle mass and changes in muscle enzymes may play an important

role in fatigue during terminal illness. The importance of changes in

the CNS, especially the reticular activating system, have been hypothesized based on reports of fatigue in patients receiving cranial radiation,

experiencing depression, or having chronic pain in the absence of

cachexia or other physiologic changes. Finally, depression and other

causes of psychological distress can contribute to fatigue.

ASSESSMENT Like pain and dyspnea, fatigue is subjective, as it

represents a patient’s sense of tiredness and decreased capacity for

physical work. Objective changes, even in body mass, may be absent.

Consequently, assessment must rely on patient self-reporting. Scales

used to measure fatigue, such as the Edmonton Functional Assessment

Tool, the Fatigue Self-Report Scales, and the Rhoten Fatigue Scale, are

usually appropriate for research but not clinical purposes. In clinical

practice, a simple performance assessment such as the Karnofsky performance status or the Eastern Cooperative Oncology Group (ECOG)’s

question “How much of the day does the patient spend in bed?” may be

the best measure. In the ECOG 0–4 performance status assessment, 0 =

normal activity; 1 = symptomatic without being bedridden; 2 = requiring some, but <50%, bed time; 3 = bedbound more than half the day;

and 4 = bedbound all the time. Such a scale allows for assessment over

time and correlates with overall disease severity and prognosis. A 2008

review by the European Association of Palliative Care also described

several longer assessment tools that contained 9–20 items, including

the Piper Fatigue Inventory, the Multidimensional Fatigue Inventory,

and the Brief Fatigue Inventory (BFI).

INTERVENTIONS Reversible causes of fatigue, such as anemia and

infection, should be treated. However, at the end of life, it must be

realistically acknowledged that fatigue will not be “cured.” The goal

is to ameliorate fatigue and help patients and families adjust expectations. Behavioral interventions should be utilized to avoid blaming the

patient for inactivity and to educate both the family and the patient that

the underlying disease causes physiologic changes that produce low

energy levels. Understanding that the problem is physiologic and not

psychological can help alter expectations regarding the patient’s level

of physical activity. Practically, this may mean reducing routine activities such as housework, cooking, and social events outside the house

and making it acceptable to receive guests while lying on a couch. At

the same time, the implementation of exercise regimens and physical

therapy can raise endorphins, reduce muscle wasting, and decrease

the risk of depression. In addition, ensuring good hydration without

worsening edema may help reduce fatigue. Discontinuing medications

that worsen fatigue may help, including cardiac medications, benzodiazepines, certain antidepressants, or opioids if the patient’s pain is

well-controlled. As end-of-life care proceeds into its final stages, fatigue

may protect patients from further suffering, and continued treatment

could be detrimental.

Only a few pharmacologic interventions target fatigue and weakness. Randomized controlled trials suggest glucocorticoids can increase

energy and enhance mood. Dexamethasone (8 mg/d) is preferred for

its once-a-day dosing and minimal mineralocorticoid activity. Benefit,

if any, is usually seen within the first month. For fatigue related to

anorexia, megestrol (480–800 mg) can be helpful. Psychostimulants

such as dextroamphetamine (5–10 mg PO) and methylphenidate

(2.5–5 mg PO) may enhance energy levels, although controlled trials

have not shown these drugs to be effective for fatigue induced by mild

and its intensity. Guidelines recommend visual analogue dyspnea

scales to assess the severity of symptoms and the effects of treatment.

Potentially reversible or treatable causes of dyspnea include infection,

pleural effusions, pulmonary emboli, pulmonary edema, asthma, and

tumor encroachment on the airway. However, the risk-versus-benefit

ratio of the diagnostic and therapeutic interventions for patients with

little time left to live must be considered carefully before undertaking

diagnostic steps. Frequently, the specific etiology cannot be identified,

and dyspnea is the consequence of progression of the underlying disease that cannot be treated. The anxiety caused by dyspnea and the

choking sensation can significantly exacerbate the underlying dyspnea

in a negatively reinforcing cycle.

INTERVENTIONS When reversible or treatable etiologies are diagnosed, they should be treated as long as the side effects of treatment,

such as repeated drainage of effusions or anticoagulants, are less burdensome than the dyspnea itself. More aggressive treatments such as

stenting a bronchial lesion may be warranted if it is clear that the dyspnea is due to tumor invasion at that site and if the patient and family

understand the risks of such a procedure.

Usually, treatment will be symptomatic (Table 12-6). Supplemental

oxygen does not appear to be effective. “A systematic review of the

literature failed to demonstrate a consistent beneficial effect of oxygen

inhalation over air inhalation for study participants with dyspnea

due to end-stage cancer or cardiac failure.” Therefore, oxygen may

be no more than an expensive placebo. Low-dose opioids reduce the

sensitivity of the central respiratory center and relieve the sensation

of dyspnea. If patients are not receiving opioids, weak opioids can be

initiated; if patients are already receiving opioids, morphine or other

stronger opioids should be used. Controlled trials do not support the

use of nebulized opioids for dyspnea at the end of life. Phenothiazines

and chlorpromazine may be helpful when combined with opioids.

Benzodiazepines can be helpful in treating dyspnea, but only if anxiety

is present. Benzodiazepines should not be used as first-line therapy or

if there is no anxiety. If the patient has a history of COPD or asthma,

inhaled bronchodilators and glucocorticoids may be helpful. If the

patient has pulmonary edema due to heart failure, diuresis with a

medication such as furosemide is indicated. Excess secretions can be

transdermally or intravenously dried with scopolamine. More general

interventions that medical staff can perform include sitting the patient

upright, removing smoke or other irritants like perfume, ensuring a

supply of fresh air with sufficient humidity, and minimizing other factors that can increase anxiety.

82PART 1 The Profession of Medicine

to moderate cancer. Doses should be given in the morning and at

noon to minimize the risk of counterproductive insomnia. Modafinil

and armodafinil, developed for narcolepsy, have shown promise in the

treatment of fatigue and have the advantage of once-daily dosing. Their

precise role in fatigue at the end of life has not been documented but

may be worth trying if other interventions are not beneficial. Anecdotal evidence suggests that L-carnitine may improve fatigue, depression, and sleep disruption.

■ PALLIATIVE SEDATION

Palliative sedation is used in distressing situations that cannot be

addressed in other ways. When patients experience severe symptoms,

such as pain or dyspnea, that cannot be relieved by conventional

interventions or experience acute catastrophic symptoms, such as

uncontrolled seizures, then palliative sedation should be considered as

an intervention of last resort. It can be abused if done to hasten death

(which it usually does not), when done at the request of the family

rather than according to the patient’s wishes, or when there are other

interventions that could still be tried. The use of palliative sedation

in cases of extreme existential or spiritual distress remains controversial. Typically, palliative sedation should be introduced only after the

patient and family have been assured that all other interventions have

been tried and after the patient and their loved ones have been able to

“say goodbye.”

Palliative sedation can be achieved by significantly increasing opioid doses until patients become unconscious and then putting them

on a continuous infusion. Another commonly used medication for

palliative sedation is midazolam at 1–5 mg IV every 5–15 min to calm

the patient, followed by a continuous IV or subcutaneous infusion of

1 mg/h. In hospital settings, a continuous propofol infusion of 5 μg/kg

per min can be used. There are also other, less commonly used medications for palliative sedation that include levomepromazine, chlorpromazine, and phenobarbital.

PSYCHOLOGICAL SYMPTOMS AND THEIR

MANAGEMENT

Depression • FREQUENCY AND IMPACT Depression at the end of

life presents an apparently paradoxical situation. Many people believe

that depression is normal among seriously ill patients because they are

dying. People frequently say, “Wouldn’t you be depressed?” Although

sadness, anxiety, anger, and irritability are normal responses to a serious condition, they are typically of modest intensity and transient.

Persistent sadness and anxiety and the physically disabling symptoms

that they can lead to are abnormal and suggestive of major depression.

The precise number of terminally ill patients who are depressed is

uncertain, primarily due to a lack of consistent diagnostic criteria and

screening. Careful follow-up of patients suggests that while as many as

75% of terminally ill patients experience depressive symptoms, ~25%

of terminally ill patients have major depression. Depression at the end

of life is concerning because it can decrease the quality of life, interfere with closure in relationships and other separation work, obstruct

adherence to medical interventions, and amplify the suffering associated with pain and other symptoms.

ETIOLOGY Previous history of depression, family history of depression or bipolar disorder, and prior suicide attempts are associated

with increased risk for depression among terminally ill patients.

Other symptoms, such as pain and fatigue, are associated with higher

rates of depression; uncontrolled pain can exacerbate depression, and

depression can cause patients to be more distressed by pain. Many

medications used in the terminal stages, including glucocorticoids, and

some anticancer agents, such as tamoxifen, interleukin 2, interferon

α, and vincristine, also are associated with depression. Some terminal

conditions, such as pancreatic cancer, certain strokes, and heart failure,

have been reported to be associated with higher rates of depression,

although this is controversial. Finally, depression may be attributable

to grief over the loss of a role or function, social isolation, or loneliness.

ASSESSMENT Unfortunately, many studies suggest that most depressed

patients at the end of life are not diagnosed, or if they are diagnosed,

they are not properly treated. Diagnosing depression among seriously

ill patients is complicated, as many of the vegetative symptoms in

the DSM-V (Diagnostic and Statistical Manual of Mental Disorders,

Fifth Edition) criteria for clinical depression—insomnia, anorexia and

weight loss, fatigue, decreased libido, and difficulty concentrating—are

associated with the process of dying itself. The assessment of depression in seriously ill patients therefore should focus on the dysphoric

mood, helplessness, hopelessness, and lack of interest, enjoyment,

and concentration in normal activities. It is now recommended that

patients near the end of life should be screened with either the PHQ-9

or the PHQ-2, which asks “Over the past 2 weeks, how often have you

been bothered by any of the following problems? (1) Little interest or

pleasure in doing things and (2) feeling down, depressed or hopeless.”

The answer categories are as follows: not at all, several days, more than

half the days, nearly every day. Other possible diagnostic tools include

the short form of the Beck Depression Index or a visual analogue scale.

Certain conditions may be confused with depression. Endocrinopathies, such as hypothyroidism and Cushing’s syndrome, electrolyte

abnormalities, such as hypercalcemia, and akathisia, especially from

dopamine-blocking antiemetics such as metoclopramide and prochlorperazine, can mimic depression and should be excluded.

INTERVENTIONS Undertreatment of depressed, terminally ill patients

is common. Physicians must treat any physical symptom, such as pain,

that may be causing or exacerbating depression. Fostering adaptation

to the many losses that the patient is experiencing can also be helpful.

Unfortunately, there are few randomized trials to guide such interventions. Thus, treatment typically follows the treatment used for

non–terminally ill depressed patients.

In the absence of randomized controlled trials, nonpharmacologic

interventions, including group or individual psychological counseling,

and behavioral therapies such as relaxation and imagery can be helpful,

especially in combination with drug therapy.

Pharmacologic interventions remain at the core of therapy. The

same medications are used to treat depression in terminally ill as in

non–terminally ill patients. Psychostimulants may be preferred for

patients with a poor prognosis or for those with fatigue or opioidinduced somnolence. Psychostimulants are comparatively fast-acting,

working within a few days instead of the weeks required for selective

serotonin reuptake inhibitors (SSRIs). Dextroamphetamine or methylphenidate should be started at 2.5–5.0 mg in the morning and at noon,

the same starting doses used for treating fatigue. The doses can eventually be escalated up to 15 mg bid. Modafinil is started at 100 mg qd

and can be increased to 200 mg if there is no effect at the lower dose.

Pemoline is a nonamphetamine psychostimulant with minimal abuse

potential. It is also effective as an antidepressant beginning at 18.75 mg

in the morning and at noon. Because it can be absorbed through the

buccal mucosa, it is preferred for patients with intestinal obstruction

or dysphagia. If it is used for prolonged periods, liver function must

be monitored. The psychostimulants can also be combined with more

traditional antidepressants while waiting for the antidepressants to

become effective, then tapered down after a few weeks if necessary.

Psychostimulants have side effects, particularly initial anxiety, insomnia, and very rarely paranoia, which may necessitate lowering the dose

or discontinuing treatment.

Mirtazapine, an antagonist at the postsynaptic serotonin receptors,

is a promising psychostimulant. It should be started at 7.5 mg before

bed and titrated up no more than once every 1–2 weeks to a maximal

dose of 45 mg/d. It has sedating, antiemetic, and anxiolytic properties,

with few drug interactions. Its side effect of weight gain may be beneficial for seriously ill patients; it is available in orally disintegrating

tablets.

For patients with a prognosis of several months or longer, SSRIs,

including fluoxetine, sertraline, paroxetine, escitalopram, and citalopram, and serotonin-noradrenaline reuptake inhibitors, such as

venlafaxine and duloxetine, are the preferred treatments, due to their

efficacy and comparatively few side effects. Because low doses of these

medications may be effective for seriously ill patients, one should use

half the usual starting dose as for healthy adults. The starting dose for