88PART 1 The Profession of Medicine

declining life-sustaining interventions, possibly including refusal of

nutrition and hydration.

■ CARE DURING THE LAST HOURS

Most laypersons have limited experiences with the actual dying process

and death. They frequently do not know what to expect of the final

hours and afterward. The family and other caregivers must be prepared, especially if the plan is for the patient to die at home.

Patients in the last days of life typically experience extreme weakness

and fatigue and become bedbound; this can lead to pressure sores. The

issue of turning patients who are near the end of life, however, must be

balanced against the potential discomfort that movement may cause.

Patients stop eating and drinking with drying of mucosal membranes

and dysphagia. Careful attention to oral swabbing, lubricants for lips,

and use of artificial tears can provide a form of care to substitute for

attempts at feeding the patient. With loss of the gag reflex and dysphagia, patients may also experience accumulation of oral secretions,

producing noises during respiration sometimes called “the death

rattle.” Scopolamine can reduce the secretions. Patients also experience changes in respiration with periods of apnea or Cheyne-Stokes

breathing. Decreased intravascular volume and cardiac output cause

tachycardia, hypotension, peripheral coolness, and livedo reticularis

(skin mottling). Patients can have urinary and, less frequently, fecal

incontinence. Changes in consciousness and neurologic function generally lead to two different paths to death.

Each of these terminal changes can cause patients and families distress, requiring reassurance and targeted interventions (Table 12-9).

Informing families that these changes might occur and providing them

with an information sheet can help preempt problems and minimize

distress. Understanding that patients stop eating because they are

dying, not dying because they have stopped eating, can reduce family

and caregiver anxiety. Similarly, informing the family and caregivers

that the “death rattle” may occur and that it is not indicative of suffocation, choking, or pain can reduce their worry from the breathing

sounds.

Families and caregivers may also feel guilty about stopping treatments, fearing that they are “killing” the patient. This may lead

to demands for interventions, such as feeding tubes, that may be

ineffective. In such cases, the physician should remind the family and

caregivers about the inevitability of events and the palliative goals.

TABLE 12-9 Managing Changes in the Patient’s Condition during the Final Days and Hours

CHANGES IN

THE PATIENT’S

CONDITION

POTENTIAL

COMPLICATION

FAMILY’S POSSIBLE

REACTION AND

CONCERN ADVICE AND INTERVENTION

Profound

fatigue

Bedbound with

development of

pressure ulcers that

are prone to infection,

malodor, and pain, and

joint pain

Patient is lazy and

giving up.

Reassure family and caregivers that terminal fatigue will not respond to interventions and should not

be resisted.

Use an air mattress if necessary.

Anorexia None Patient is giving up;

patient will suffer

from hunger and will

starve to death.

Reassure family and caregivers that the patient is not eating because he or she is dying; not eating

at the end of life does not cause suffering or death.

Forced feeding, whether oral, parenteral, or enteral, does not reduce symptoms or prolong life.

Dehydration Dry mucosal

membranes (see below)

Patient will suffer

from thirst and die of

dehydration.

Reassure family and caregivers that dehydration at the end of life does not cause suffering because

patients lose consciousness before any symptom distress.

Intravenous hydration can worsen symptoms of dyspnea by pulmonary edema and peripheral edema

as well as prolong the dying process.

Dysphagia Inability to swallow oral

medications needed for

palliative care

Do not force oral intake.

Discontinue unnecessary medications that may have been continued, including antibiotics,

diuretics, antidepressants, and laxatives.

If swallowing pills is difficult, convert essential medications (analgesics, antiemetics, anxiolytics,

and psychotropics) to oral solutions, buccal, sublingual, or rectal administration.

“Death

rattle”—noisy

breathing

Patient is choking

and suffocating.

Reassure the family and caregivers that this is caused by secretions in the oropharynx and the

patient is not choking.

Reduce secretions with scopolamine (0.2–0.4 mg SC q4h or 1–3 patches q3d).

Reposition patient to permit drainage of secretions.

Do not suction. Suction can cause patient and family discomfort and is usually ineffective.

Apnea,

Cheyne-Stokes

respirations,

dyspnea

Patient is

suffocating.

Reassure family and caregivers that unconscious patients do not experience suffocation or air

hunger.

Apneic episodes are frequently a premorbid change.

Opioids or anxiolytics may be used for dyspnea.

Oxygen is unlikely to relieve dyspneic symptoms and may prolong the dying process.

Urinary or fecal

incontinence

Skin breakdown if days

until death

Potential transmission

of infectious agents to

caregivers

Patient is dirty,

malodorous, and

physically repellent.

Remind family and caregivers to use universal precautions.

Frequent changes of bedclothes and bedding.

Use diapers, urinary catheter, or rectal tube if diarrhea or high urine output.

Agitation or

delirium

Day/night reversal

Hurt self or caregivers

Patient is in horrible

pain and going to

have a horrible

death.

Reassure family and caregivers that agitation and delirium do not necessarily connote physical pain.

Depending on the prognosis and goals of treatment, consider evaluating for causes of delirium and

modifying medications.

Manage symptoms with haloperidol, chlorpromazine, diazepam, or midazolam.

Dry mucosal

membranes

Cracked lips, mouth

sores, and candidiasis

can also cause pain.

Odor

Patient may be

malodorous,

physically repellent.

Use baking soda mouthwash or saliva preparation q15–30 min.

Use topical nystatin for candidiasis.

Coat lips and nasal mucosa with petroleum jelly q60–90 min.

Use ophthalmic lubricants q4h or artificial tears q30 min.

Palliative and End-of-Life Care

89CHAPTER 12

Interventions may prolong the dying process and cause discomfort.

Physicians also should emphasize that withholding treatments is both

legal and ethical and that the family members are not the cause of the

patient’s death. This reassurance may have to be provided multiple

times.

Hearing and touch are said to be the last senses to stop functioning.

Whether this is the case or not, families and caregivers can be encouraged to communicate with the dying patient. Encouraging them to

talk directly to the patient, even if he or she is unconscious, and hold

the patient’s hand or demonstrate affection in other ways can be an

effective way to channel their urge “to do something” for the patient.

When the plan is for the patient to die at home, the physician must

inform the family and caregivers how to determine that the patient has

died. The cardinal signs are cessation of cardiac function and respiration; the pupils become fixed; the body becomes cool; muscles relax;

and incontinence may occur. Remind the family and caregivers that the

eyes may remain open even after the patient has died.

The physician should establish a plan for who the family or caregivers will contact when the patient is dying or has died. Without a

plan, family members may panic and call 911, unleashing a cascade

of unwanted events, from arrival of emergency personnel and resuscitation to hospital admission. The family and caregivers should be

instructed to contact the hospice (if one is involved), the covering physician, or the on-call member of the palliative care team. They should

also be told that the medical examiner need not be called unless the

state requires it for all deaths. Unless foul play is suspected, the health

care team need not contact the medical examiner either.

Just after the patient dies, even the best-prepared family may experience shock and loss and be emotionally distraught. They need time

to assimilate the event and be comforted. Health care providers are

likely to find it meaningful to write a bereavement card or letter to

the family. The purpose is to communicate about the patient, perhaps

emphasizing the patient’s virtues and the honor it was to care for the

patient, and to express concern for the family’s hardship. Some physicians attend the funerals of their patients. Although this is beyond any

medical obligation, the presence of the physician can be a source of

support to the grieving family and provides an opportunity for closure

for the physician.

Death of a spouse is a strong predictor of poor health, and even mortality, for the surviving spouse. It may be important to alert the spouse’s

physician about the death so that he or she is aware of symptoms that

might require professional attention.

■ FURTHER READING

Emanuel E et al: Attitudes and practices of euthanasia and physicianassisted suicide in the United States, Canada, and Europe. JAMA

316:79, 2016.

Kelley AS, Meier DE: Palliative care—A shifting paradigm. N Engl J

Med 363:781, 2010.

Kelley AS et al: Hospice enrollment saves money for Medicare and

improves care quality across a number of different lengths-of-stay.

Health Aff 32:552, 2012.

Kelley AS et al: Palliative care for the seriously ill. N Engl J Med

373:747, 2015.

Mack JW et al: Associations between end-of-life discussion characteristics and care received near death: A prospective cohort study. J Clin

Oncol 30:4387, 2012.

Murray SA et al: Illness trajectories and palliative care. BMJ 330:1007,

2005.

Neuman P et al: Medicare per capita spending by age and service: New

data highlights oldest beneficiaries. Health Aff (Millwood) 34:335,

2015.

Nicholas LH et al: Regional variation in the association between

advance directives and end-of-life Medicare expenditures. JAMA

306:1447, 2011.

Ornstein KA et al: Evaluation of racial disparities in hospice use and

end-of-life treatment intensity in the REGARDS cohort. JAMA Netw

Open 3(8):e2014639, 2020.

Quinn KL et al: Association of receipt of palliative care interventions

with health care use, quality of life, and symptom burden among

adults with chronic noncancer illness: A systematic review and

meta-analysis. JAMA 324:1439, 2020.

Teno JM et al: Change in end-of-life care for medicare beneficiaries:

Site of death, place of care, and health transitions in 2000, 2005, and

2009. JAMA 309:470, 2013.

Teno JM et al: Site of death, place of care, and health care transitions

among US Medicare beneficiaries, 2000-2015. JAMA 320:264, 2018.

Van Den Beuken-VanEverdingen MH et al: Update on prevalence

of pain in patients with cancer: Systematic review and meta-analysis.

J Pain Symptom Manage 51:1070, 2016.

WEBSITES

American Academy of Hospice and Palliative Medicine: www.

aahpm.org

Center to Advance Palliative Care: http://www.capc.org

Education in Palliative and End of Life Care (EPEC): http://

www.epec.net

Family Caregiver Alliance: http://www.caregiver.org

National Hospice and Palliative Care Organization (including

state-specific advance directives): http://www.nhpco.org

Nccn: The National Comprehensive Cancer Network palliative care

guidelines: http://www.nccn.org

Our Care Wishes Advance Care Planning Tool: https://www.

ourcarewishes.org

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Section 1 Pain

Cardinal Manifestations and Presentation of Diseases PART 2

13 Pain: Pathophysiology

and Management

James P. Rathmell, Howard L. Fields

The province of medicine is to preserve and restore health and to

relieve suffering. Understanding pain is essential to both of these goals.

Because pain is universally understood as a signal of disease, it is the

most common symptom that brings a patient to a physician’s attention.

The function of the pain sensory system is to protect the body and

maintain homeostasis. It does this by detecting, localizing, and identifying potential or actual tissue-damaging processes. Because different

diseases produce characteristic patterns of tissue damage, the quality,

time course, and location of a patient’s pain lend important diagnostic

clues. It is the physician’s responsibility to assess each patient promptly

for any remediable cause underlying the pain and to provide rapid and

effective pain relief whenever possible.

THE PAIN SENSORY SYSTEM

Pain is an unpleasant sensation localized to a part of the body. It is

often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a

bodily or emotional reaction (e.g., terrifying, nauseating, sickening).

Furthermore, any pain of moderate or higher intensity is accompanied

by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion.

When it is acute, pain is characteristically associated with behavioral

arousal and a stress response consisting of increased blood pressure,

heart rate, pupil diameter, and plasma cortisol levels. In addition, local

muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often

present.

■ PERIPHERAL MECHANISMS

The Primary Afferent Nociceptor A peripheral nerve consists

of the axons of three different types of neurons: primary sensory

afferents, motor neurons, and sympathetic postganglionic neurons

(Fig. 13-1). The cell bodies of primary sensory afferents are located

in the dorsal root ganglia within the

vertebral foramina. The primary afferent

axon has two branches: one projects centrally into the spinal cord and the other

projects peripherally to innervate tissues.

Primary afferents are classified by their

diameter, degree of myelination, and

conduction velocity. The largest diameter afferent fibers, A-beta (Aβ), respond

maximally to light touch and/or moving

stimuli; they are present primarily in

nerves that innervate the skin. In normal

individuals, the activity of these fibers

does not produce pain. There are two

other classes of primary afferent nerve

fibers: the small diameter myelinated

A-delta (Aδ) and the unmyelinated (C)

axons (Fig. 13-1). These fibers are present in nerves to the skin and to deep

somatic and visceral structures. Some

tissues, such as the cornea, are innervated only by Aδ and C fiber afferents.

Most Aδ and C fiber afferents respond maximally to intense (painful)

stimuli and produce the subjective experience of pain when they

are activated; this defines them as primary afferent nociceptors (pain

receptors). The ability to detect painful stimuli is completely abolished

when conduction in Aδ and C fiber axons is blocked.

Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond

to heat; intense cold; intense mechanical distortion, such as a pinch;

changes in pH, particularly an acidic environment; and application of

chemical irritants including adenosine triphosphate (ATP), serotonin,

bradykinin (BK), and histamine. The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the vanilloid receptor, mediates perception of some noxious stimuli, especially

heat sensations, by nociceptive neurons; it is activated by heat, acidic

pH, endogenous mediators, and capsaicin, a component of hot chili

peppers.

Sensitization When intense, repeated, or prolonged stimuli are

applied to damaged or inflamed tissues, the threshold for activating

primary afferent nociceptors is lowered, and the frequency of firing

is higher for all stimulus intensities. Inflammatory mediators such as

BK, nerve-growth factor, some prostaglandins (PGs), and leukotrienes

contribute to this process, which is called sensitization. Sensitization

occurs at the level of the peripheral nerve terminal (peripheral sensitization) as well as at the level of the dorsal horn of the spinal cord

(central sensitization). Peripheral sensitization occurs in damaged or

inflamed tissues, when inflammatory mediators activate intracellular signal transduction in nociceptors, prompting an increase in the

production, transport, and membrane insertion of chemically gated

and voltage-gated ion channels. These changes increase the excitability of nociceptor terminals and lower their threshold for activation

by mechanical, thermal, and chemical stimuli. Central sensitization

occurs when activity, generated by nociceptors during inflammation,

enhances the excitability of nerve cells in the dorsal horn of the spinal

cord. Following injury and resultant sensitization, normally innocuous

stimuli can produce pain (termed allodynia). Sensitization is a clinically important process that contributes to tenderness, soreness, and

hyperalgesia (increased pain intensity in response to the same noxious

stimulus; e.g., pinprick causes severe pain). A striking example of sensitization is sunburned skin, in which severe pain can be produced by

a gentle slap or a warm shower.

Sensitization is of particular importance for pain and tenderness

in deep tissues. Viscera are normally relatively insensitive to noxious

mechanical and thermal stimuli, although hollow viscera do generate

Peripheral nerve

Dorsal root

ganglion

Spinal

cord

Sympathetic

postganglionic

Aβ

Aδ

C

Sympathetic

preganglionic

FIGURE 13-1 Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary

afferents with cell bodies in the dorsal root ganglion and sympathetic postganglionic fibers with cell bodies in the

sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ), small-diameter myelinated

(Aδ), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.

92PART 2 Cardinal Manifestations and Presentation of Diseases

significant discomfort when distended. In contrast, when affected by

a disease process with an inflammatory component, deep structures

such as joints or hollow viscera characteristically become exquisitely

sensitive to mechanical stimulation.

A large proportion of Aδ and C fiber afferents innervating viscera

are completely insensitive in normal noninjured, noninflamed tissue.

That is, they cannot be activated by known mechanical or thermal

stimuli and are not spontaneously active. However, in the presence of

inflammatory mediators, these afferents become sensitive to mechanical stimuli. Such afferents have been termed silent nociceptors, and

their characteristic properties may explain how, under pathologic

conditions, the relatively insensitive deep structures can become the

source of severe and debilitating pain and tenderness. Low pH, PGs,

leukotrienes, and other inflammatory mediators such as BK play a

significant role in sensitization.

Nociceptor-Induced Inflammation Primary afferent nociceptors are not simply passive messengers of threats to tissue injury but also

play an active role in tissue protection through a neuroeffector function. Most nociceptors contain polypeptide mediators, including substance P, calcitonin gene related peptide (CGRP), and cholecystokinin,

that are released from their peripheral terminals when they are activated (Fig. 13-2). Substance P is an 11-amino-acid peptide that is

released in peripheral tissues from primary afferent nociceptors and

has multiple biologic activities. It is a potent vasodilator, causes mast

cell degranulation, is a chemoattractant for leukocytes, and increases

the production and release of inflammatory mediators. Interestingly,

depletion of substance P from joints reduces the severity of experimental arthritis.

■ CENTRAL MECHANISMS

The Spinal Cord and Referred Pain The axons of primary

afferent nociceptors enter the spinal cord via the dorsal root. They

terminate in the dorsal horn of the spinal gray matter (Fig. 13-3).

The terminals of primary afferent axons contact spinal neurons that

transmit the pain signal to brain sites involved in pain perception.

When primary afferents are activated by noxious stimuli, they release

neurotransmitters from their terminals that excite the spinal cord neurons. The major neurotransmitter released is glutamate, which rapidly

excites the second-order dorsal horn neurons. Primary afferent nociceptor terminals also release substance P and CGRP, which produce a

slower and longer-lasting excitation of the dorsal horn neurons. The

axon of each primary afferent contacts many spinal neurons, and each

spinal neuron receives convergent inputs from many primary afferents.

The convergence of sensory inputs to a single spinal pain-transmission

neuron is of great importance because it underlies the phenomenon of

referred pain. All spinal neurons that receive input from the viscera

and deep musculoskeletal structures also receive input from the skin.

The convergence patterns are determined by the spinal segment of the

dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are

derived from the third and fourth cervical dorsal root ganglia. Primary

afferents with cell bodies in these same ganglia supply the skin of the

shoulder and lower neck. Thus, sensory inputs from both the shoulder

skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments. Because of this

convergence and the fact that the spinal neurons are most often activated

by inputs from the skin, activity evoked in spinal neurons by input from

deep structures is often mislocalized by the patient to a bodily location

that roughly corresponds with the region of skin innervated by the same

spinal segment. Thus, inflammation near the central diaphragm is

often reported as shoulder discomfort. This spatial displacement of

pain sensation from the site of the injury that produces it is known as

referred pain.

Ascending Pathways for Pain A majority of spinal neurons

contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic

tract, which lies in the anterolateral white matter of the spinal cord,

the lateral edge of the medulla, and the lateral pons and midbrain.

The spinothalamic pathway is crucial for pain sensation in humans.

Interruption of this pathway produces permanent deficits in pain and

temperature discrimination.

Spinothalamic tract axons ascend to several regions of the thalamus.

There is tremendous divergence of the pain signal from these thalamic

sites to several distinct areas of the cerebral cortex that subserve different aspects of the pain experience (Fig. 13-4). One of the thalamic

projections is to the somatosensory cortex. This projection mediates

the sensory discriminative aspects of pain, i.e., its location, intensity,

and quality. Other thalamic neurons project to cortical regions that

are linked to emotional responses, such as the cingulate and insular

cortex. These pathways to the frontal cortex subserve the affective or

unpleasant emotional dimension of pain. This affective dimension of

pain produces suffering and exerts potent control of behavior. Because

of this dimension, fear is a constant companion of pain. As a consequence, injury or surgical lesions to areas of the frontal cortex activated

by painful stimuli can diminish the emotional impact of pain while

Primary activation

Secondary activation

A

B

Platelet

Mast cell

SP H

5HT

SP

BK

PG

K+

BK

H+

FIGURE 13-2 Events leading to activation, sensitization, and spread of sensitization

of primary afferent nociceptor terminals. A. Direct activation by intense pressure

and consequent cell damage. Cell damage induces lower pH (H+

) and leads to

release of potassium (K+

) and to synthesis of prostaglandins (PGs) and bradykinin

(BK). PGs increase the sensitivity of the terminal to BK and other pain-producing

substances. B. Secondary activation. Impulses generated in the stimulated terminal

propagate not only to the spinal cord but also into other terminal branches where

they induce the release of peptides, including substance P (SP). Substance P causes

vasodilation and neurogenic edema with further accumulation of BK. Substance P

also causes the release of histamine (H) from mast cells and serotonin (5HT) from

platelets.

 

Palliative and End-of-Life Care

85CHAPTER 12

caregivers should be identified through local sources or nationally

through groups such as the National Family Caregivers Association

(www.nfcacares.org), the American Cancer Society (www.cancer.org),

and the Alzheimer’s Association (www.alz.org).

■ EXISTENTIAL NEEDS AND THEIR MANAGEMENT

Frequency Religion and spirituality are often important to dying

patients. Nearly 70% of patients report becoming more religious or

spiritual when they became terminally ill, and many find comfort in

religious or spiritual practices such as prayer. However, ~20% of terminally ill patients become less religious, frequently feeling cheated or

betrayed by becoming terminally ill. For other patients, the need is for

existential meaning and purpose that is distinct from, and may even be

antithetical to, religion or spirituality. When asked, patients and family

caregivers frequently report wanting their professional caregivers to be

more attentive to religion and spirituality.

Assessment Health care providers are often hesitant about involving themselves in the religious, spiritual, and existential experiences

of their patients because it may seem private or not relevant to the

current illness. But physicians and other members of the care team

should be able at least to detect spiritual and existential needs. Screening questions have been developed for a physician’s spiritual history

taking. Spiritual distress can amplify other types of suffering and

even masquerade as intractable physical pain, anxiety, or depression.

The screening questions in the comprehensive assessment are usually

sufficient. Deeper evaluation and intervention are rarely appropriate

for the physician unless no other member of a care team is available

or suitable. Pastoral care providers may be helpful, whether from the

medical institution or from the patient’s own community.

Interventions Precisely how religious practices, spirituality, and

existential explorations can be facilitated and improve end-of-life care

is not well established. What is clear is that for physicians, one main

intervention is to inquire about the role and importance of spirituality and religion in a patient’s life. This will help a patient feel heard

and help physicians identify specific needs. In one study, only 36%

of respondents indicated that a clergy member would be comforting.

Nevertheless, the increase in religious and spiritual interest among a

substantial fraction of dying patients suggests inquiring of individual

patients how this need can be addressed. Some evidence supports specific methods of addressing existential needs in patients, ranging from

establishing a supportive group environment for terminal patients to

individual treatments emphasizing a patient’s dignity and sources of

meaning.

MANAGING THE LAST STAGES

■ PALLIATIVE CARE SERVICES: HOW AND WHERE

Determining the best approach to providing palliative care to patients

will depend on patient preferences, the availability of caregivers and

specialized services in close proximity, institutional resources, and

reimbursement. Hospice is a leading, but not the only, model of palliative care services. In the United States, slightly more than a third—

35.7%—of hospice care is provided in private residential homes with

14.5% of hospice care in nursing homes. In the United States, Medicare

pays for hospice services under Part A, the hospital insurance part

of reimbursement. Two physicians must certify that the patient has a

prognosis of ≤6 months if the disease runs its usual course. Prognoses

are probabilistic by their nature; patients are not required to die within

6 months but rather to have a condition from which half the individuals with it would not be alive within 6 months. Patients sign a hospice

enrollment form that states their intent to forgo curative services

related to their terminal illness but can still receive medical services

for other comorbid conditions. Patients also can withdraw enrollment

and reenroll later; the hospice Medicare benefit can be revoked later

to secure traditional Medicare benefits. Payments to the hospice are

per diem (or capitated), not fee-for-service. Payments are intended

to cover physician services for the medical direction of the care team;

regular home care visits by registered nurses and licensed practical

nurses; home health aide and homemaker services; chaplain services;

social work services; bereavement counseling; and medical equipment,

supplies, and medications. No specific therapy is excluded, and the goal

is for each therapy to be considered for its symptomatic (as opposed to

disease-modifying) effect. Additional clinical care, including services

of the primary physician, is covered by Medicare Part B even while the

hospice Medicare benefit is in place.

The Affordable Care Act directs the secretary of Health and Human

Services to gather data on Medicare hospice reimbursement with the

goal of reforming payment rates to account for resource use over an

entire episode of care. The legislation also requires additional evaluations and reviews of eligibility for hospice care by hospice physicians

or nurses. The Center for Medicare and Medicaid Innovation (CMMI)

sponsors and carries out demonstration projects to test models and

evaluate the potential of new methods. In 2016, CMMI started a 5-year

test of concurrent hospice and palliative care services with curative

treatment for terminally ill patients who have a life expectancy of

≤6 months. A 4-year test initiated in 2021 will examine the inclusion of

hospice in Medicare Advantage covering 8% of the market and include

important health plans.

By 2018, the average length of enrollment in a hospice for Medicare

beneficiaries was 90 days. However, the median length of stay was

just 18 days, suggesting most patients are in hospice for a short time.

Such short stays create barriers to establishing high-quality palliative

services in patients’ homes and also place financial strains on hospice

providers since the initial assessments are resource intensive. Physicians should initiate early referrals to the hospice to allow more time

for patients to receive palliative care.

In the United States, hospice care has been the main method for

securing palliative services for terminally ill patients. However, leading

physicians have increasingly emphasized the need to introduce palliative care much earlier in patients’ illness, and efforts are being made

to develop palliative care services that can be provided before the last

6 months of life and across a variety of settings. Studies of terminally

ill patients indicate that those who received in-home palliative care

delivered by an interdisciplinary team compared to usual care were

more satisfied, more likely to die at home, and had fewer visits to the

emergency room and lower per-day costs. More companies and home

health agencies are now offering nonhospice palliative care services

in patients’ homes in an effort to increase quality of life and forestall

emergency room visits and hospitalizations. Similarly, palliative care

services are increasingly available via consultation, rather than being

available only in hospital, day care, outpatient, and nursing home

settings. Palliative care consultations for nonhospice patients can be

billed as for other consultations under Medicare Part B. It is argued

that using palliative care earlier in patients’ illness allows patients and

family members to become more acculturated to avoiding life-sustaining treatments, facilitating a smoother transition to hospice care closer

to death.

■ WITHDRAWING AND WITHHOLDING

LIFE-SUSTAINING TREATMENT

Legal Aspects For centuries, it has been deemed ethical to withhold or withdraw life-sustaining interventions. The current legal consensus in the United States and most wealthy countries is that patients

have a moral as well as legal right to refuse medical interventions.

American courts also have held that incompetent patients have a right

to refuse medical interventions. For patients who are incompetent and

terminally ill and who have not completed an advance care directive,

next of kin can exercise that right, although this may be restricted in

some states, depending on how clear and convincing the evidence

is of the patient’s preferences. Courts have limited families’ ability to

terminate life-sustaining treatments in patients who are conscious and

incompetent but not terminally ill. In theory, patients’ right to refuse

medical therapy can be limited by four countervailing interests: (1)

preservation of life, (2) prevention of suicide, (3) protection of third

parties such as children, and (4) preservation of the integrity of the

86PART 1 The Profession of Medicine

medical profession. In practice, these interests almost never override

the right of competent patients and incompetent patients who have left

explicit wishes or advance care directives.

For incompetent patients who either appointed a proxy without

specific indications of their wishes or never completed an advance

care directive, three criteria have been suggested to guide the decision

to terminate medical interventions. First, some commentators suggest

that ordinary care should be administered but extraordinary care could

be terminated. Because the ordinary/extraordinary distinction is too

vague, courts and commentators widely agree that it should not be used

to justify decisions about stopping treatment. Second, many courts

have advocated the use of the substituted-judgment criterion, which

holds that the proxy decision-makers should try to imagine what the

incompetent patient would do if he or she were competent. However,

multiple studies indicate that many proxies, even close family members, cannot accurately predict what the patient would have wanted.

Therefore, substituted judgment becomes more of a guessing game

than a way of fulfilling the patient’s wishes. Finally, the best-interests

criterion holds that proxies should evaluate treatments by balancing

their benefits and risks and select those treatments where the benefits

maximally outweigh the burdens of treatment. Clinicians have a clear

and crucial role in this by carefully and dispassionately explaining the

known benefits and burdens of specific treatments. Yet even when that

information is as clear as possible, different individuals can have very

different views of what is in the patient’s best interests, and families

may have disagreements or even overt conflicts. This criterion has

been criticized because there is no single way to determine the balance

between benefits and burdens; it depends on a patient’s personal values. For instance, for some people, being alive even if mentally incapacitated is a benefit, whereas for others, it may be the worst possible

existence. As a matter of practice, physicians rely on family members to

make decisions that they feel are best and object only if those decisions

seem to demand treatments that the physicians consider not beneficial.

Practices Withholding and withdrawing acutely life-sustaining

medical interventions from terminally ill patients are now standard

practice. More than 90% of American patients die without cardiopulmonary resuscitation (CPR), and just as many forgo other potentially

life-sustaining interventions. For instance, in ICUs in the period of

1987–1988, CPR was performed 49% of the time, but it was performed

only 10% of the time in 1992–1993 and on just 1.8% of admissions

from 2001 to 2008. On average, 3.8 interventions, such as vasopressors

and transfusions, were stopped for each dying ICU patient. However,

up to 19% of decedents in hospitals received interventions such as

extubation, ventilation, and surgery in the 48 h preceding death. There

is wide variation in practices among hospitals and ICUs, suggesting

an important element of physician preferences rather than consistent

adherence to professional society recommendations.

Mechanical ventilation may be the most challenging intervention

to withdraw. The two approaches are terminal extubation, which is

the removal of the endotracheal tube, and terminal weaning, which

is the gradual reduction of the fraction of inspired oxygen (FIO2

) or

ventilator rate. One-third of ICU physicians prefer to use the terminal

weaning technique, and 13% extubate; the majority of physicians utilize

both techniques. The American Thoracic Society’s 2008 clinical policy

guidelines note that there is no single correct process of ventilator

withdrawal and that physicians use and should be proficient in both

methods but that the chosen approach should carefully balance benefits and burdens as well as patient and caregiver preferences. Some

recommend terminal weaning because patients do not develop upper

airway obstruction and the distress caused by secretions or stridor;

however, terminal weaning can prolong the dying process and not

allow a patient’s family to be with the patient unencumbered by an

endotracheal tube. To ensure comfort for conscious or semiconscious

patients before withdrawal of the ventilator, neuromuscular blocking

agents should be terminated and sedatives and analgesics administered.

Removing the neuromuscular blocking agents permits patients to show

discomfort, facilitating the titration of sedatives and analgesics; it also

permits interactions between patients and their families. A common

practice is to inject a bolus of midazolam (2–4 mg) or lorazepam

(2–4 mg) before withdrawal, followed by a bolus of 5–10 mg of morphine and continuous infusion of morphine (50% of the bolus dose per

hour) during weaning. In patients who have significant upper airway

secretions, IV scopolamine at a rate of 100 μg/h can be administered.

Additional boluses of morphine or increases in the infusion rate should

be administered for respiratory distress or signs of pain. Higher doses

will be needed for patients already receiving sedatives and opioids.

The median time to death after stopping of the ventilator is 1 h.

However, up to 10% of patients unexpectedly survive for 1 day or more

after mechanical ventilation is stopped. Women and older patients

tend to survive longer after extubation. Families need to be reassured

about both the continuations of treatments for common symptoms,

such as dyspnea and agitation, after withdrawal of ventilatory support

and the uncertainty of length of survival after withdrawal of ventilatory

support.

■ FUTILE CARE

Beginning in the late 1980s, some commentators argued that physicians could terminate futile treatments demanded by the families of

terminally ill patients. Although no objective definition or standard

of futility exists, several categories have been proposed. Physiologic

futility means that an intervention will have no physiologic effect.

Some have defined qualitative futility as applying to procedures that

“fail to end a patient’s total dependence on intensive medical care.”

Quantitative futility occurs “when physicians conclude (through personal experience, experiences shared with colleagues, or consideration

of reported empiric data) that in the last 100 cases, a medical treatment

has been useless.” The term conceals subjective value judgments about

when a treatment is “not beneficial.” Deciding whether a treatment that

obtains an additional 6 weeks of life or a 1% survival advantage confers benefit depends on patients’ preferences and goals. Furthermore,

physicians’ predictions of when treatments are futile deviate markedly

from the quantitative definition. When residents thought CPR was

quantitatively futile, more than one in five patients had a >10% chance

of survival to hospital discharge. Most studies that purport to guide

determinations of futility are based on insufficient data and therefore

cannot provide statistical confidence for clinical decision-making.

Quantitative futility rarely applies in ICU settings.

Many commentators reject using futility as a criterion for withdrawing care, preferring instead to consider futility situations as ones that

represent conflict that calls for careful negotiation between families

and health care providers. The American Medical Association and

other professional societies have developed process-based approaches

to resolving cases clinicians feel are futile. These process-based measures mainly suggest involving consultants and/or ethics committees

when there are seemingly irresolvable differences. Some hospitals have

enacted “unilateral do-not-resuscitate” policies to allow clinicians to

provide a do-not-resuscitate order in cases in which consensus cannot

be reached with families and medical opinion is that resuscitation

would be futile if attempted. This type of a policy is not a replacement

for careful and patient communication and negotiation but recognizes

that agreement cannot always be reached.

In 1999, Texas enacted the so-called Futile Care Act. Other states,

such as Virginia, Maryland, and California, have also enacted such

laws that provide physicians a “safe harbor” from liability if they

refuse a patient’s or family’s request for life-sustaining interventions.

For instance, in Texas, when a disagreement about terminating

interventions between the medical team and the family has not been

resolved by an ethics consultation, the physician is tasked with trying

to facilitate transfer of the patient to an institution willing to provide

treatment. If this fails after 10 days, the hospital and physician may unilaterally withdraw treatments determined to be futile. The family may

appeal to a state court. Early data suggest that the law increases futility

consultations for the ethics committee and that, although most families

concur with withdrawal, ~10–15% of families refuse to withdraw treatment. As of 2007, there had been 974 ethics committee consultations

on medical futility cases and 65 in which committees ruled against

families and gave notice that treatment would be terminated. In 2007,

Palliative and End-of-Life Care

87CHAPTER 12

a survey of Texas hospitals showed that 30% of hospitals had used the

futility law in 213 adult cases and 42 pediatric cases. Treatment was

withdrawn for 27 of those patients, and the remainder were transferred

to other facilities or died while awaiting transfer.

■ EUTHANASIA AND PHYSICIAN-ASSISTED SUICIDE

Euthanasia and PAS are defined in Table 12-8. Terminating lifesustaining care and providing opioid medications to manage symptoms

such as pain or dyspnea have long been considered ethical by the medical profession and legal by courts and should not be conflated with

euthanasia or PAS.

Legal Aspects Euthanasia and PAS are legal in the Netherlands,

Belgium, Luxembourg, Colombia, Canada, Spain, Western Australia,

and New Zealand. Euthanasia was legalized in the Northern Territory

of Australia in 1996, but that legislation was repealed 9 months

later in 1997. Under certain conditions, a layperson in Switzerland or

Germany can legally elect assisted suicide. In the United States, PAS is

legal in Washington, D.C., and 10 states: Oregon, Washington State,

Montana, Vermont, California, Colorado, Hawaii, Maine, New Jersey,

and New Mexico. No state in the United States has legalized euthanasia.

In the United States, multiple criteria must be met for PAS: the patient

must have a terminal condition of <6 months and must be determined

eligible through a process that includes a 15-day waiting period. In

2009, the state supreme court of Montana ruled that state law permits

PAS for terminally ill patients. Many other countries, such as Portugal,

are actively debating the legalization of euthanasia and/or PAS.

Practices Fewer than 10–20% of terminally ill patients actually

consider euthanasia and/or PAS for themselves. Use of euthanasia and

PAS is increasing but remains relatively rare. In all countries, even the

Netherlands and Belgium where these practices have been tolerated

and legal for many years, <5% of death occur by euthanasia or PAS. As

of the most recent data, 4.7% of all deaths were by euthanasia or PAS

in the Netherlands (2015) and 4.6% in Belgium (2013). Just 0.50% of all

deaths in Oregon in 2019 (188 of 37,397 deaths) and 0.36% of all deaths

in Washington State in 2018 (203 of 56,913 deaths) were reported to be

by PAS, although these may be underestimates since the cause of some

deaths of patients who received medications could not be verified.

In Belgium, the Netherlands, Oregon, and Washington, >70% of

patients utilizing these interventions are dying of cancer; <10% of

deaths by euthanasia or PAS involve patients with AIDS or amyotrophic

TABLE 12-8 Definitions of Physician-Assisted Suicide and Euthanasia

TERM DEFINITION LEGAL STATUS

Voluntary active

euthanasia

Intentionally administering

medications or other

interventions to cause the

patient’s death with the patient’s

informed consent

Netherlands, Belgium,

Luxembourg, Canada,

Colombia, Spain,

Western Australia, New

Zealand

Involuntary

active

euthanasia

Intentionally administering

medications or other

interventions to cause the

patient’s death when the patient

was competent to consent but

did not—e.g., the patient may not

have been asked

Nowhere

Passive

euthanasia

Withholding or withdrawing lifesustaining medical treatments

from a patient to let him or her

die (terminating life-sustaining

treatments)

Everywhere

Physicianassisted suicide

A physician provides medications

or other interventions to a patient

with the understanding that the

patient can use them to commit

suicide

Netherlands, Belgium,

Luxembourg, Canada,

Colombia, Germany,

Switzerland, Oregon,

Washington, Montana,

Vermont, California,

Colorado, District of

Columbia, Hawaii, Maine,

New Jersey, New Mexico

lateral sclerosis. While the numbers are small, in the Netherlands, the

numbers of euthanasia or PAS cases in patients with psychiatric disorders, dementia, and the accumulation of health issues are increasing.

Pain is not the primary motivator for patients’ requests for or interest in euthanasia and/or PAS. Among the first patients to receive PAS

in Oregon, only 1 of the 15 patients had inadequate pain control, compared with 15 of the 43 patients in a control group who experienced

inadequate pain relief. About 33% of patients in Oregon seeking PAS

currently cite pain or fear of pain as their main reason for doing so.

Conversely, depression and hopelessness are strongly associated with

patient interest in euthanasia and PAS. Concerns about loss of dignity

or autonomy or being a burden on family members appear to be more

important factors motivating a desire for euthanasia or PAS. Losing

autonomy (87% Oregon [OR], 85% Washington [WA]), not being able

to enjoy activities (90% OR, 84% WA), and fear of losing dignity (72%

OR, 69% WA) are the most-cited end-of-life concerns in both states.

A high percentage of patients seeking PAS note being a burden on

family (59% OR, 51% WA). A study from the Netherlands showed that

depressed terminally ill cancer patients were four times more likely

to request euthanasia and confirmed that uncontrolled pain was not

associated with greater interest in euthanasia.

Euthanasia and PAS are no guarantee of a painless, quick death.

Data from the Netherlands indicate that in as many as 20% of euthanasia and PAS cases technical and other problems arose, including

patients waking from coma, not becoming comatose, regurgitating

medications, and experiencing a prolonged time to death. Data from

Oregon between 1998 and 2017 and Washington between 2009 and

2017 indicate that of patients who received PAS prescriptions, 81%

died at home and prescribers were present in 9.7% of cases. The time

between drug intake and coma ranged from 1 min to 11 h, and the time

from drug intake to death ranged from 1 min to 104 h. The median

time from ingestion to coma was 5 min and from ingestion to death

was 25 min. In Oregon between 1998 and 2015, 53% of patients had no

complications, 44% of patients had no data on complications, and 2.4%

of patients had regurgitation after taking the prescribed medicine as

the only complication. In addition, six patients awakened. In Washington

State between 2014 and 2015, 1.4% of patients had regurgitation, one

patient had a seizure, and the reported range of time to death extended

to 30 h. In the Netherlands, problems were significantly more common

in PAS, sometimes requiring the physician to intervene and provide

euthanasia.

Regardless of whether they practice in a setting where euthanasia

is legal or not, many physicians over the course of their careers will

receive a patient request for euthanasia or PAS. In the United States,

18% of physicians have received a request for PAS and 11% have

received a request for euthanasia. Three percent complied with a

request for PAS, while 5% complied with a request for euthanasia. In

the Netherlands, where the practices are legal, 77% of physicians have

received a request for PAS or euthanasia and 60% have performed these

interventions.

Competency in dealing with such a request is crucial. Although

challenging, the request can also provide a chance to address intense

suffering. After receiving a request for euthanasia and/or PAS, health

care providers should carefully clarify the request with empathic, openended questions to help elucidate the underlying cause for the request,

such as, “What makes you want to consider this option?” Endorsing

either moral opposition or moral support for the act tends to be counterproductive, giving an impression of being judgmental or of endorsing the idea that the patient’s life is worthless. Health care providers

must reassure the patient of continued care and commitment. The

patient should be educated about alternative, less laden options, such

as symptom management and withdrawing any unwanted treatments,

and the reality of euthanasia and/or PAS, since the patient may have

misconceptions about their effectiveness as well as the legal implications of the choice. Depression, hopelessness, and other symptoms of

psychological distress, as well as physical suffering and economic burdens, are likely factors motivating the request, and such factors should

be assessed and treated aggressively. After these interventions and

clarification of options, most patients proceed with another approach,

 

Palliative and End-of-Life Care

83CHAPTER 12

fluoxetine is 10 mg once a day. In most cases, once-a-day dosing is

possible. The choice of which SSRI to use should be driven by (1) the

patient’s past success or failure with the specific medication and (2) the

most favorable side effect profile for that specific agent. For instance,

for a patient in whom fatigue is a major symptom, a more activating

SSRI (fluoxetine) would be appropriate. For a patient in whom anxiety

and sleeplessness are major symptoms, a more sedating SSRI (paroxetine) would be appropriate. Importantly, it can take up to 4 weeks for

these drugs to have an effect.

Atypical antidepressants are recommended only in select circumstances, usually with the assistance of a specialty consultation.

Trazodone can be an effective antidepressant but is sedating and can

cause orthostatic hypotension and, occasionally, priapism. Therefore,

it should be used before bed and only when a sedating effect is desired

and is often used for patients with insomnia at a dose starting at 25 mg.

Bupropion can also be used. In addition to its antidepressant effects,

bupropion is energizing, making it useful for depressed patients who

experience fatigue. However, it can cause seizures, preventing its use

for patients with a risk of CNS neoplasms or terminal delirium. Finally,

alprazolam, a benzodiazepine, starting at 0.25–1.0 mg tid, can be effective in seriously ill patients who have a combination of anxiety and

depression. Although it is potent and works quickly, it has many drug

interactions and may cause delirium, especially among very ill patients,

because of its strong binding to the benzodiazepine–γ-aminobutyric

acid (GABA) receptor complex.

Unless used as adjuvants for the treatment of pain, tricyclic antidepressants are not recommended. While they can be effective, their

therapeutic window and serious side effects typically limit their utility.

Similarly, monoamine oxidase (MAO) inhibitors are not recommended because of their side effects and dangerous drug interactions.

Delirium (See Chap. 27) • FREQUENCY In the weeks or months

before death, delirium is uncommon, although it may be significantly

underdiagnosed. However, delirium becomes relatively common in the

days and hours immediately before death. Up to 85% of patients dying

from cancer may experience terminal delirium.

ETIOLOGY Delirium is a global cerebral dysfunction characterized by

alterations in cognition and consciousness. It is frequently preceded

by anxiety, changes in sleep patterns (especially reversal of day and

night), and decreased attention. In contrast to dementia, delirium has

an acute onset, is characterized by fluctuating consciousness and inattention, and is reversible, although reversibility may be more theoretical than real for patients near death. Delirium may occur in a patient

with dementia; indeed, patients with dementia are more vulnerable to

delirium.

Causes of delirium include metabolic encephalopathy arising from

liver or renal failure, hypoxemia, or infection; electrolyte imbalances

such as hypercalcemia; paraneoplastic syndromes; dehydration; and

primary brain tumors, brain metastases, or leptomeningeal spread of

tumor. Among dying patients, delirium is commonly caused by side

effects of treatments, including radiation for brain metastases and

medications, such as opioids, glucocorticoids, anticholinergic drugs,

antihistamines, antiemetics, benzodiazepines, and chemotherapeutic

agents. The etiology may be multifactorial; e.g., dehydration may exacerbate opioid-induced delirium.

ASSESSMENT Delirium should be recognized in any terminally ill

patient exhibiting new onset of disorientation, impaired cognition,

somnolence, fluctuating levels of consciousness, or delusions with or

without agitation. Delirium must be distinguished from acute anxiety,

depression, and dementia. The central distinguishing feature is altered

consciousness, which usually is not noted in anxiety, depression, or

dementia. Although “hyperactive” delirium, characterized by overt

confusion and agitation, is probably more common, patients should

also be assessed for “hypoactive” delirium, which is characterized by

sleep-wake reversal and decreased alertness.

In some cases, use of formal assessment tools such as the MiniMental Status Examination (which does not distinguish delirium from

dementia) and the Delirium Rating Scale (which does distinguish

delirium from dementia) may be helpful in distinguishing delirium

from other processes. The patient’s list of medications must be evaluated carefully. Nonetheless, a reversible etiologic factor for delirium is

found in fewer than half of all terminally ill patients. Given that most

terminally ill patients experiencing delirium are very close to death and

often at home, extensive diagnostic evaluations such as lumbar punctures and neuroradiologic examinations are inappropriate.

INTERVENTIONS One of the most important objectives of terminal

care is to provide terminally ill patients the lucidity to say goodbye to

the people they love. Delirium, especially when in combination with

agitation during the final days, is distressing to family and caregivers. A

strong determinant of bereavement difficulties is witnessing a difficult

death. Thus, terminal delirium should be treated aggressively.

At the first sign of delirium, such as day-night reversal with slight

changes in mentation, the physician should let the family members

know that it is time to be sure that everything they want to say has

been said. The family should be informed that delirium is common

just before death.

If medications are suspected of being a cause of the delirium, unnecessary agents should be discontinued. Other potentially reversible

causes, such as constipation, urinary retention, and metabolic abnormalities, should be treated. Supportive measures aimed at providing a

familiar environment should be instituted, including restricting visits

only to individuals with whom the patient is familiar and eliminating

new experiences; orienting the patient, if possible, by providing a clock

and calendar; and gently correcting the patient’s hallucinations or cognitive mistakes.

Pharmacologic management focuses on the use of neuroleptics and,

in extreme cases, anesthetics (Table 12-7). Haloperidol remains the

first-line therapy. Usually, patients can be controlled with a low dose

(1–3 mg/d), given every 6 h, although some may require as much as

20 mg/d. Haloperidol can be administered PO, SC, or IV. IM injections should not be used, except when this is the only way to address

a patient’s delirium. Olanzapine, an atypical neuroleptic, has shown

significant effectiveness in completely resolving delirium in cancer

patients. It also has other beneficial effects for terminally ill patients,

including antinausea, antianxiety, and weight gain. Olanzapine is

useful for patients with longer anticipated life expectancies because

it is less likely to cause dysphoria and has a lower risk of dystonic

reactions. Additionally, because olanzapine is metabolized through

multiple pathways, it can be used in patients with hepatic and renal

dysfunction. Olanzapine has the disadvantage that it is only available

orally and takes a week to reach steady state. The usual dose is 2.5–5 mg

PO bid. Chlorpromazine (10–25 mg every 4–6 h) can be useful if

sedation is desired and can be administered IV or PR in addition to

PO. Dystonic reactions resulting from dopamine blockade are a side

effect of neuroleptics, although they are reported to be rare when these

drugs are used to treat terminal delirium. If patients develop dystonic

reactions, benztropine should be administered. Neuroleptics may be

TABLE 12-7 Medications for the Management of Delirium

INTERVENTIONS DOSE

Neuroleptics

Haloperidol 0.5–5 mg q2–12h, PO/IV/SC/IM

Thioridazine 10–75 mg q4–8h, PO

Chlorpromazine 12.5–50 mg q4–12h, PO/IV/IM

Atypical neuroleptics

Olanzapine 2.5–5 mg qd or bid, PO

Risperidone 1–3 mg q12h, PO

Anxiolytics

Lorazepam 0.5–2 mg q1–4h, PO/IV/IM

Midazolam 1–5 mg/h continuous infusion, IV/SC

Anesthetics

Propofol 0.3–2.0 mg/h continuous infusion, IV

84PART 1 The Profession of Medicine

combined with lorazepam to reduce agitation when the delirium is the

result of alcohol or sedative withdrawal.

If no response to first-line therapy is observed, a specialty consultation should be obtained with a goal to change to a different medication.

If the patient fails to improve after a second neuroleptic, sedation with

either an anesthetic such as propofol or continuous-infusion midazolam may be necessary. By some estimates, as many as 25% of patients

at the very end of life who experience delirium, especially restless delirium with myoclonus or convulsions, may require sedation.

Physical restraints should be used with great reluctance and only when

patients’ violence is threatening to themselves or others. If restraints are

used, their appropriateness should be frequently reevaluated.

Insomnia • FREQUENCY Sleep disorders, defined as difficulty

initiating sleep or maintaining sleep, sleep difficulty at least 3 nights a

week, or sleep difficulty that causes impairment of daytime functioning, occurs in 19–63% of patients with advanced cancer. Some 30–74%

of patients with other end-stage conditions, including AIDS, heart

disease, COPD, and renal disease, experience insomnia.

ETIOLOGY Patients with cancer may experience changes in sleep efficiency, such as an increase in stage I sleep. Insomnia may also coexist

with both physical illnesses, like thyroid disease, and psychological illnesses, like depression and anxiety. Medications, including antidepressants, psychostimulants, glucocorticoids, and β agonists, are significant

contributors to sleep disorders, as are caffeine and alcohol. Multiple

over-the-counter medications contain caffeine and antihistamines,

which can contribute to sleep disorders.

ASSESSMENT Assessments should include specific questions concerning sleep onset, sleep maintenance, and early-morning wakening, as

these will provide clues to both the causative agents and management

of insomnia. Patients should be asked about previous sleep problems,

screened for depression and anxiety, and asked about symptoms of

thyroid disease. Caffeine and alcohol are prominent causes of sleep

problems, and a careful history of the use of these substances should

be obtained. Both excessive use and withdrawal from alcohol can be

causes of sleep problems.

INTERVENTIONS The mainstays of any intervention include improvement of sleep hygiene (encouragement of regular time for sleep,

decreased nighttime distractions, elimination of caffeine and other

stimulants and alcohol), interventions to treat anxiety and depression,

and treatment for the insomnia itself. For patients with depression who

have insomnia and anxiety, a sedating antidepressant such as mirtazapine can be helpful. In the elderly, trazodone, beginning at 25 mg at

nighttime, is an effective sleep aid at doses lower than those that cause

its antidepressant effect. Zolpidem may have a decreased incidence

of delirium in patients compared with traditional benzodiazepines,

but this has not been clearly established. When benzodiazepines are

prescribed, short-acting ones (such as lorazepam) are favored over longeracting ones (such as diazepam). Patients who receive these medications

should be observed for signs of increased confusion and delirium.

■ SOCIAL NEEDS AND THEIR MANAGEMENT

Financial Burdens • FREQUENCY Dying can impose substantial

economic strains on patients and families, potentially causing distress.

This is known as financial toxicity. In the United States, which has the

least comprehensive health insurance systems among wealthy countries, a quarter of families coping with end-stage cancer report that care

was a major financial burden and a third used up most of their savings. Among Medicare beneficiaries, average out-of-pocket costs were

>$8000. Between 10% and 30% of families are forced to sell assets, use

savings, or take out a mortgage to pay for the patient’s health care costs.

The patient is likely to reduce hours worked and eventually stop

working altogether. In 20% of cases, a family member of the terminally

ill patient also must stop working to provide care. The major underlying causes of economic burden are related to poor physical functioning and care needs, such as the need for housekeeping, nursing, and

personal care. More debilitated patients and poor patients experience

greater economic burdens.

INTERVENTION The economic burden of end-of-life care should

not be ignored as a private matter. It has been associated with a

number of adverse health outcomes, including preferring comfort

care over life-prolonging care, as well as consideration of euthanasia

or physician-assisted suicide (PAS). Economic burdens increase the

psychological distress of the families and caregivers of terminally ill

patients, and poverty is associated with many adverse health outcomes.

Importantly, studies have found that “patients with advanced cancer

who reported having end-of-life conversations with physicians had significantly lower health care costs in their final week of life. Higher costs

were associated with worse quality of death.” Assistance from a social

worker, early on if possible, to ensure access to all available benefits

may be helpful. Many patients, families, and health care providers are

unaware of options for long-term care insurance, respite care, the Family Medical Leave Act (FMLA), and other sources of assistance. Some

of these options (such as respite care) may be part of a formal hospice

program, but others (such as the FMLA) do not require enrollment in

a hospice program.

Relationships • FREQUENCY Settling personal issues and closing

the narrative of lived relationships are universal needs. When asked if

sudden death or death after an illness is preferable, respondents often

initially select the former, but soon change to the latter as they reflect

on the importance of saying goodbye. Bereaved family members who

have not had the chance to say goodbye often have a more difficult

grief process.

INTERVENTIONS Care of seriously ill patients requires efforts to facilitate the types of encounters and time spent with family and friends

that are necessary to meet those needs. Family and close friends may

need to be accommodated in hospitals and other facilities with unrestricted visiting hours, which may include sleeping near the patient,

even in otherwise regimented institutional settings. Physicians and

other health care providers may be able to facilitate and resolve strained

interactions between the patient and other family members. Assistance

for patients and family members who are unsure about how to create

or help preserve memories, whether by providing materials such as a

scrapbook or memory box or by offering them suggestions and informational resources, can be deeply appreciated. Taking photographs and

creating videos can be especially helpful to terminally ill patients who

have younger children or grandchildren.

Family Caregivers • FREQUENCY Caring for seriously ill patients

places a heavy burden on families. Families are frequently required to

provide transportation and homemaking, as well as other services.

Typically, paid professionals, such as home health nurses and hospice

workers, supplement family care; only about a quarter of all caregiving

consists of exclusively paid professional assistance. Over the past 40

years, there has been a significant decline in the United States of deaths

occurring in hospitals, with a simultaneous increase in deaths in other

facilities and at home. Over a third of deaths occur in patients’ homes.

This increase in out-of-hospital deaths increases reliance on families

for end-of-life care. Increasingly, family members are being called upon

to provide physical care (such as moving and bathing patients) and

medical care (such as assessing symptoms and giving medications) in

addition to emotional care and support.

Three-quarters of family caregivers of terminally ill patients are

women—wives, daughters, sisters, and even daughters-in-law. Since

many are widowed, women tend to be able to rely less on family for

caregiving assistance and may need more paid assistance. About 20% of

terminally ill patients report substantial unmet needs for nursing and

personal care. The impact of caregiving on family caregivers is substantial: both bereaved and current caregivers have a higher mortality rate

than that of non-caregiving controls.

INTERVENTIONS It is imperative to inquire about unmet needs and

to try to ensure that those needs are met either through the family or

by paid professional services when possible. Community assistance

through houses of worship or other community groups often can be

mobilized by telephone calls from the medical team to someone the

patient or family identifies. Sources of support specifically for family

 

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

 

Palliative and End-of-Life Care

77CHAPTER 12

will and designates a proxy is often used, and the directive should

indicate clearly whether the specified patient preferences or the proxy’s

choice takes precedence if they conflict. Some states have begun to

put into practice a “Physician Orders for Life-Sustaining Treatment

(POLST)” directive, which builds on communication between providers and patients by including guidance for end-of-life care in a

color-coordinated form that follows the patient across treatment

settings. The procedures for completing advance care planning documents vary according to state law.

A potentially misleading distinction relates to statutory, as opposed

to advisory, documents. Statutory documents are drafted to fulfill relevant state laws. Advisory documents are drafted to reflect the patient’s

wishes. Both are legal, the former under state law and the latter under

common or constitutional law.

LEGAL ASPECTS As of 2021, 48 states and the District of Columbia

had enacted living will legislation. Massachusetts and Michigan are the

two states without living will legislation. Indiana has a life-prolonging

procedures declaration. States differ in the requirements for advanced

directives, including whether they need to be witnessed and, if so, by

how many witnesses and whether they need to be notarized. Importantly, in 25 states, the laws state that the living will is not valid if a

woman is pregnant. All states except Alaska have enacted durable

power of attorney for health care laws that permit patients to designate

a proxy decision-maker with authority to terminate life-sustaining

treatments. Only in Alaska does the law prohibit proxies from terminating life-sustaining treatments for pregnant women.

The U.S. Supreme Court has ruled that patients have a constitutional

right to decide any issues related to refusing or terminating medical

interventions, including life-sustaining interventions, and that mentally incompetent patients can exercise this right by providing “clear

and convincing evidence” of their preferences. Since advance care

directives permit patients to provide such evidence, commentators

agree that they are constitutionally protected. Most commentators

believe that a state is required to honor any clear advance care directive,

regardless of whether it is written on an “official” form. Many states

have enacted laws for the explicit purpose of honoring out-of-state

directives. If a patient is not using a statutory form, it may be advisable

to attach a statutory form to the advance care directive being used.

State-specific forms are readily available free of charge for health care

providers, patients, and families through the website of the National

Hospice and Palliative Care Organization (http://www.nhpco.org).

REIMBURSEMENT As of January 1, 2016, the Centers for Medicare

and Medicaid Services amended the physician fee schedule to reimburse discussions of advance care planning under Current Procedural

Terminology codes 99497 and 99498. The session must be voluntary

and include an explanation of advance care planning but need not

include a completed advance care document. There can be multiple

bills for the discussion if it extends over several encounters. A study

found that patients who engaged in a billed advance care planning

encounter were more likely to be enrolled in hospice and less likely to

receive intensive therapies, despite being more likely to be hospitalized in the ICU. However, a billing incentive in and of itself may not

increase advance care planning discussions by clinicians. In 2016, just

1.6% of Medicare Advantage patients had a discussion of advance care

planning that was billed. Factors beyond reimbursement, such as clinicians’ lack of comfort and skill in carrying out advance care planning

discussions and lack of time, appear to impede discussions of advance

care planning.

INTERVENTIONS

■ PHYSICAL SYMPTOMS AND THEIR MANAGEMENT

Great emphasis has been placed on addressing dying patients’ pain.

In order to emphasize its importance, pain assessment has frequently

been included as the fifth vital sign. Heightened consideration of pain

has been advocated by large health care systems such as the Veterans’

Administration and accrediting bodies such as The Joint Commission. Although this embrace of pain has been symbolically important,

available data suggest that making pain the fifth vital sign does not lead

to improved pain management practices. In light of the opioid crisis in

the United States, the emphasis on pain management has begun to be

reexamined. For instance, in 2017 draft standards, The Joint Commission recommends nonpharmacologic pain treatment as well as identification of psychosocial risk factors for addiction. Importantly, good

palliative care requires much more than good pain management. The

frequency of symptoms varies by disease and other factors. The most

common physical and psychological symptoms among all terminally ill

patients include pain, fatigue, insomnia, anorexia, dyspnea, depression,

anxiety, nausea, and vomiting. In the last days of life, terminal delirium

is also common. Assessments of patients with advanced cancer have

shown that patients experienced an average of 11.5 different physical

and psychological symptoms (Table 12-4).

In the vast majority of cases, evaluations to determine the etiology

of these symptoms should be limited to the history and physical examination. In some cases, radiologic or other diagnostic examinations will

provide sufficient benefit in directing optimal palliative care to warrant

the risks, potential discomfort, and inconvenience, especially to a seriously ill patient. Only a few of the common symptoms that present difficult management issues will be addressed in this chapter. Additional

information on the management of other symptoms, such as nausea

and vomiting, insomnia, and diarrhea, can be found in Chaps. 45,

31, and 46, respectively. Information on the management of patients

with cancer is provided in Chap. 69.

Pain • FREQUENCY The frequency of pain among terminally ill

patients varies significantly. Cancer (~85%), congestive heart failure

(CHF; ~75%), and AIDS have been associated with a higher prevalence of pain compared to other advanced illnesses, such as COPD

(~45%), chronic kidney disease (~40%), and dementia (~40%). One

meta-analysis of adults with advanced or terminal illness found pain

prevalence of 30–94% in patients with cancer, compared to 21–77% for

COPD, 14–78% for CHF, 11–83% for end-stage renal disease, 14–63%

for dementia, and 30–98% for AIDS.

ETIOLOGY There are two types of pain: nociceptive and neuropathic.

Nociceptive pain is further divided into somatic or visceral pain.

Somatic pain is the result of direct mechanical or chemical stimulation

of nociceptors and normal neural signaling to the brain. It tends to

be localized, aching, throbbing, and cramping. The classic example

is bone metastases. Visceral pain is caused by nociceptors in gastrointestinal (GI), respiratory, and other organ systems. It is a deep or

colicky type of pain classically associated with pancreatitis, myocardial

infarction, or tumor invasion of viscera. Neuropathic pain arises from

TABLE 12-4 Common Physical and Psychological Symptoms of

Terminally Ill Patients

PHYSICAL SYMPTOMS PSYCHOLOGICAL SYMPTOMS

Pain Anxiety

Fatigue and weakness Depression

Dyspnea Hopelessness

Insomnia Meaninglessness

Dry mouth Irritability

Anorexia Impaired concentration

Nausea and vomiting Confusion

Constipation Delirium

Cough Loss of libido

Swelling of arms or legs

Itching

Diarrhea

Dysphagia

Dizziness

Fecal and urinary incontinence

Numbness/tingling in hands/feet

78PART 1 The Profession of Medicine

disordered nerve signals. It is described by patients as burning, electrical, or shock-like pain. Classic examples are post-stroke pain, tumor

invasion of the brachial plexus, and herpetic neuralgia.

ASSESSMENT Pain is a subjective experience. Depending on the

patient’s circumstances, perspective, and physiologic condition, the

same physical lesion or disease state can produce different levels of

reported pain and need for pain relief. Systematic assessment includes

eliciting the following: (1) type: throbbing, cramping, burning, etc.; (2)

periodicity: continuous, with or without exacerbations, or incident; (3)

location; (4) intensity; (5) modifying factors; (6) effects of treatments;

(7) functional impact; and (8) impact on patient. Several validated pain

assessment measures may be used, including the Visual Analogue Scale

(VAS), the Brief Pain Inventory (BPI), or the Numerical Pain Rating

Scale (NRS-11). Other scales have been developed for neuropathic

pain, such as the Neuropathic Pain Scale and the DN4 Questionnaire.

Frequent reassessments on a consistent scale are essential to assess the

impact of and need to readjust interventions.

INTERVENTIONS Interventions for pain must be tailored to each

individual, with the goal of preempting chronic pain and relieving

breakthrough pain. At the end of life, there is rarely reason to doubt

a patient’s report of pain. With the opioid crisis in the United States,

there is more emphasis on making opioids one component of multimodal analgesia. Nevertheless, at the end of life, pain medications,

especially opioids, remain the cornerstone of management (Fig. 12-2).

If they are failing and nonpharmacologic interventions—including

radiotherapy and anesthetic or neurosurgical procedures such as

peripheral nerve blocks or epidural medications—are required, a pain

consultation is appropriate.

Pharmacologic interventions still largely follow the World Health

Organization three-step, “analgesic ladder” approach, which involves

nonopioid analgesics, “mild” opioids, and “strong” opioids, with or

without adjuvants (Chap. 13). Nonopioid analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs), are the initial treatments for

mild pain. They work primarily by inhibiting peripheral prostaglandins

and reducing inflammation but may also have central nervous system

(CNS) effects. Additionally, NSAIDs have a ceiling effect. Ibuprofen,

up to 2400 mg/d qid, has a minimal risk of causing bleeding and renal

impairment and is a good initial choice. In patients with a history of

severe GI or other bleeding, however, ibuprofen should be avoided.

In patients with a history of mild gastritis or gastroesophageal reflux

disease (GERD), acid-lowering therapy, such as a proton pump inhibitor, should be used. Acetaminophen is an alternative in patients with

a history of GI bleeding and can be used safely at up to 4 g/d qid. In

patients with liver dysfunction due to metastases or other causes and in

patients with heavy alcohol use, doses should be reduced.

If nonopioid analgesics are insufficient, opioids should be introduced. Opioids primarily work by interacting with μ opioid receptors

to activate pain-inhibitory neurons in the CNS, although they also

interact variably with δ and κ receptors. Receptor agonists, such

as morphine, codeine, and fentanyl, produce analgesia by activating pain-inhibitory neurons in the CNS. Partial agonists, such as

buprenorphine, have a ceiling effect for analgesia and a lower potential

for abuse. They are useful for postacute pain but should not be used for

chronic pain in end-of-life care. Pure antagonists, such as naloxone and

methylnaltrexone, are used for reversal of opioid effects.

Traditionally, “weak” opioids such as codeine were used first. If they

failed to relieve pain after dose escalation, “strong” opioids like morphine were used in doses of 5–10 mg every 4 h. However, this breakdown between “weak” and “strong” opioids is no longer commonly

accepted, with smaller doses of “stronger” opioids frequently being

preferred over similar or larger doses of “weaker” opioids, and different

pain syndromes having different preferred therapies. Regardless, nonopioid analgesics should be combined with opioids, as they potentiate

the effect of opioids.

Importantly, the goal is to prevent patients from experiencing pain.

Consequently, for continuous pain, opioids should be administered on

a regular, around-the-clock basis consistent with their duration of analgesia, and the next dose should occur before the effect of the previous

dose wears off. They should not be provided only when the patient

MILD PAIN

Acetaminophen: 500 mg 2 tablets every 4–6 h

Ibuprofen: 400 mg every 6 h; max 8 tablets per day

(2400 mg/d qid)

MODERATE PAIN

Codeine: 30–60 mg every 4–8 h; maximum daily

dose for pain 240 mg

Tramadol: 25 mg PO every 6 h; max 400 mg/d

Add to acetaminophen, NSAIDs

SEVERE PAIN

Morphine: 2.5–5 mg every 3–6 h orally

Hydromorphone: 1–2 mg every 3–6 h orally

Fentanyl transdermal: 1000-µg patch for 72 h

Hydrocodone: 5–10 mg every 3–6 h orally

Add to acetaminophen, NSAIDs

Pain persists or increases

Difficult to Control Pain

Specialist Consultation

(Consideration of surgical procedures such as nerve

blocks)

Pain persists or increases

NEUROPATHIC PAIN

burning, electrical, shock-like

e.g., poststroke pain, tumor invasion of brachial plexus, herpetic

neuralgia

Treatment

Gabapentin: 100–300 mg bid or tid, with 50–100% dose increments

every 3 days; 3600 mg/d in 2 or 3 days

NOCICEPTIVE PAIN

cramping, throbbing, aching, sharp, prickling, stabbing, deep and

constant, dull and gnawing

e.g., pancreatitis, bone metastases, tumor invasion, obstruction (of

ureters, colon, gastric outlet, gallbladder, etc.)

Treatment

NSAIDs or acetaminophen with opioids

FIGURE 12-2 Terminal pain management flow chart. NSAIDs, nonsteroidal anti-inflammatory drugs.

Palliative and End-of-Life Care

79CHAPTER 12

experiences pain. Patients should also be provided rescue medication,

such as liquid morphine, for breakthrough pain, generally at 20% of

the baseline dose. Patients should be informed that using the rescue

medication does not obviate the need to take the next standard dose

of pain medication. If the patient’s pain remains uncontrolled after

24 h and recurs before the next dose, requiring the patient to utilize

the rescue medication, the daily opioid dose can be increased by the

total dose of rescue medications used by the patient, or by 50% of the

standing opioid daily dose for moderate pain and 100% for severe pain.

It is inappropriate to start with extended-release preparations.

Instead, an initial focus on using short-acting preparations to determine how much is required in the first 24–48 h will allow clinicians to

determine opioid needs. Once pain relief is obtained using short-acting

preparations, the switch should be made to extended-release preparations. Even with a stable extended-release preparation regimen, the

patient may experience incident pain, such as during movement or

dressing changes. Short-acting preparations should be taken before

such predictable episodes. Although less common, patients may have

“end-of-dose failure” with long-acting opioids, meaning that they

develop pain after 8 h in the case of an every-12-h medication. In

these cases, a trial of giving an every-12-h medication every 8 h is

appropriate.

Due to differences in opioid receptors, cross-tolerance among opioids is incomplete, and patients may experience different side effects

with different opioids. Therefore, if a patient is not experiencing pain

relief or is experiencing too many side effects, a change to another opioid preparation is appropriate. When switching, one should begin with

50–75% of the published equianalgesic dose of the new opioid.

Unlike NSAIDs, opioids have no ceiling effect; therefore, there is no

maximum dose, no matter how many milligrams the patient is receiving. The appropriate dose is the dose needed to achieve pain relief. This

is an important point for clinicians to explain to patients and families.

Addiction or excessive respiratory depression is extremely unlikely in

the terminally ill; fear of these side effects should neither prevent escalating opioid medications when the patient is experiencing insufficient

pain relief nor justify using opioid antagonists.

Opioid side effects should be anticipated and treated preemptively.

Nearly all patients experience constipation that can be debilitating (see

below). Failure to prevent constipation often results in noncompliance

with opioid therapy. The preferred treatment is prevention. Cathartics

(senna 2 tbsp qHS), stool softeners (docusate 100 mg PO qd), and/or

laxatives (laxtulose 30 mL qd) are considered first-line treatment. For

refractory cases, opioid antagonists or other therapies, such as lubiprostone, should be considered.

Methylnaltrexone is the best-studied opioid antagonist for use in

refractory opioid-induced constipation. It reverses opioid-induced

constipation by blocking peripheral opioid receptors, but not central

receptors, for analgesia. In placebo-controlled trials, it has been shown

to cause laxation within 24 h of administration. As with the use of

opioids, about a third of patients using methylnaltrexone experience

nausea and vomiting, but unlike with opioid usage, tolerance usually

develops within a week. Therefore, when one is beginning opioids, an

antiemetic such as metoclopramide or a serotonin antagonist is often

prescribed prophylactically and stopped after 1 week. Olanzapine has

also been shown to have antinausea properties and can be effective

in countering delirium or anxiety, with the advantage of some weight

gain.

Drowsiness, a common side effect of opioids, also usually abates

within a week. For refractory or severe cases, pharmacologic therapy

should be considered. The best-studied agents are the psychostimulants dextroamphetamine, methylphenidate, and modafinil, although

evidence regarding their efficacy is weak. Modafinil has the advantage

of once-a-day dosing compared to methyphenidate’s twice daily dosing.

Seriously ill patients who require chronic pain relief rarely become

addicted. Suspicion of addiction should not be a reason to withhold

pain medications from terminally ill patients. Nonetheless, patients

and families may withhold prescribed opioids for fear of addiction

or dependence. Physicians and health care providers should reassure

patients and families that the patient will not become addicted to

opioids if they are used as prescribed for pain relief; this fear should

not prevent the patient from taking the medications around the clock.

However, diversion of drugs for use by other family members or illicit

sale may occur. It may be necessary to advise the patient and caregiver

about secure storage of opioids. Contract writing with the patient and

family can help. If that fails, transfer to a safe facility may be necessary.

Tolerance describes the need to increase medication dosage for the

same pain relief without a concurrent change in disease. In the case of

patients with advanced disease, the need for increasing opioid dosage

for pain relief usually is caused by disease progression rather than tolerance. Physical dependence is indicated by symptoms resulting from

the abrupt withdrawal of opioids and should not be confused with

addiction.

In recent years, the potential dangers of opioid drugs have become

increasingly apparent. To help mitigate the risk of these powerful

drugs, several strategies should be used to reduce the risk of aberrant

drug use. To start, all patients should be assessed for their individual

levels of risk. While there are multiple surveys available, including the

Opioid Risk Tool, none have gained widespread use or validation. In

general, however, it is important to screen for prior substance abuse

and major psychiatric disorders.

For patients deemed to be high risk, a multidisciplinary effort

should be pursued to reduce the risk of adverse consequences, such

as addiction and diversion. Prescribing strategies include selecting

opioids with longer durations of action and lower street values, such

as methadone, and prescribing smaller quantities with more frequent

follow-up. Monitoring options include periodic urine screening and

referral to pain specialists. In some cases, it may also be reasonable to

consider not offering short-acting opioids for breakthrough pain. In no

situation, however, should adequate pain relief be withheld due to risk.

Adjuvant analgesic medications are nonopioids that potentiate the

analgesic effects of opioids. They are especially important in the management of neuropathic pain. Gabapentin, an anticonvulsant initially

studied in the setting of herpetic neuralgia, is now the first-line treatment for neuropathic pain resulting from a variety of causes. It is begun

at 100–300 mg bid or tid, with 50–100% dose increments every 3 days.

Usually 900–3600 mg/d in two or three doses is effective. The combination of gabapentin and nortriptyline may be more effective than gabapentin alone. Two potential side effects of gabapentin to be aware of are

confusion and drowsiness, especially in the elderly. Other effective

adjuvant medications include pregabalin, which has the same mechanism of action as gabapentin but is absorbed more efficiently from

the GI tract. Lamotrigine is a novel agent whose mechanism of action

is unknown but has been shown to be effective. It is recommended

to begin at 25–50 mg/d, increasing to 100 mg/d. Carbamazepine, a

first-generation agent, has been proven effective in randomized trials

for neuropathic pain. Other potentially effective anticonvulsant adjuvants include topiramate (25–50 mg qd or bid, rising to 100–300 mg/d)

and oxcarbazepine (75–300 mg bid, rising to 1200 mg bid).

Glucocorticoids, preferably dexamethasone given once a day, can be

useful in reducing inflammation that causes pain, while also elevating

mood, energy, and appetite. Its main side effects include confusion,

sleep difficulties, and fluid retention. Glucocorticoids are especially

effective for bone pain and abdominal pain from distention of the GI

tract or liver. Other drugs, including clonidine and baclofen, can be

effective in providing pain relief. These drugs are adjuvants and generally should be used in conjunction with—not instead of—opioids.

Methadone, carefully dosed because of its unpredictable half-life in

many patients, has activity at the N-methyl-D-aspartamate (NMDA)

receptor and is useful for complex pain syndromes and neuropathic

pain. It is generally reserved for cases in which first-line opioids

(morphine, oxycodone, hydromorphone) are either ineffective or

unavailable.

Radiation therapy can treat bone pain from single metastatic lesions.

Bone pain from multiple metastases can be amenable to radiopharmaceuticals such as strontium-89 and samarium-153. Bisphosphonates,

such as pamidronate (90 mg every 4 weeks) and calcitonin (200 IU

intranasally once or twice a day), also provide relief from bone pain but

have multiday onsets of action.