ACP medicine, 3rd Edition

Clinical Essentials

Symptom Management in Palliative Medicine

Maria Torroella Carney MD1

Jennifer Rhodes-Kropf MD2

Assistant Professor of Medicine

1Geriatrics and Adult Development, Mount Sinai School of Medicine

2Albert Einstein College of Medicine of Yeshiva University; Director, Department of Inpatient Services, Divison of Geriatrics, Montefiore Hospital

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

July 2006

The goal of palliative care is to provide comfort and support for both patient and family through the course of a life-threatening illness. Symptom control is essential to meeting that goal. This chapter discusses symptoms that commonly contribute to patients' suffering in terminal illness: pain; respiratory, gastrointestinal, mouth, and skin problems; and delirium.

Although this chapter focuses on physical and psychological symptoms, achieving symptom control requires the physician to address the patient's suffering in all its aspects: physical, psychological, social, and spiritual. Physical distress cannot be effectively treated in isolation from the emotional and spiritual components that contribute to it, nor can these sources of suffering be addressed adequately when patients are in physical distress. The various components of suffering must be addressed simultaneously [see CE:XI Management of Psychosocial Issues in Terminal Illness].

Symptom Assessment

A full and formal symptom assessment is necessary before effective treatment can be instituted.1 Symptoms are inherently subjective2; therefore, patient self-reporting must be the primary source of information, and the clinician must believe what the patient says. If the patient is unable to report, a family member or professional can provide a surrogate assessment. However, several studies have demonstrated that observer and patient assessments are not well correlated.3,4

To compensate for this inherent subjectivity, researchers have developed symptom measurement systems that are intended to quantify patients' perceptions in a manner that is valid and reliable. These systems have the further benefit of eliciting symptoms that the patient might not have volunteered. In one study of palliative care patients, the median number of symptoms found using systematic assessment was 10-fold higher than that found on open-ended questioning.5

Often, symptom measurement systems have taken the form of symptom checklists.6,7 For example, the Edmonton Symptom Assessment Scale6 comprises 14 questions that evaluate eight physical and psychological symptoms [see Table 1]. This scale has been extensively employed in palliative care research, in part because of its ease of use. Although the scale yields a numerical score (the higher the score, the more severe the patient's condition), the formal scoring mechanism is used only in research. In clinical practice, the scale can be used informally to evaluate a patient's status and follow it over time.

Table 1 Modified Edmonton Symptom Assessment Scale6

1a. Please rate your pain now.

1. □ No pain

2. □ Mild pain

3. □ Moderate pain

4. □ Severe pain

1b. Please rate your pain over the past 3 days.

1. □ No pain

2. □ Mild pain

3. □ Moderate pain

4. □ Severe pain

1c. Is your pain control acceptable to you?

1. □ Very acceptable

2. □ Acceptable

3. □ Not acceptable

2. How would you describe your activity level over the past 3 days?

1. □ Very active

2. □ Somewhat active

3. □ Minimally active

4. □ Not active

3. How would you describe your amount of nausea over the past 3 days?

1. □ Not nauseated

2. □ Mildly nauseated

3. □ Moderately nauseated

4. □ Very nauseated

4a. How would you describe your level of constipation over the past 3 days?

1. □ No constipation

2. □ Mild constipation

3. □ Moderate constipation

4. □ Severe constipation

4b. When was your last bowel movement?

1. □ Today

2. □ Yesterday

3. □ 2–3 days ago

4. □ More than 4 days ago

  5. How would you describe your feelings of depression over the past 3 days?

1. □ Not depressed

2. □ Mildly depressed

3. □ Moderately depressed

4. □ Very depressed

6. How would you describe your feelings of anxiety over the past 3 days?

1. □ Not anxious

2. □ Mildly anxious

3. □ Moderately anxious

4. □ Very anxious

7. How would you describe your level of fatigue over the past 3 days?

1. □ Not fatigued

2. □ Mildly fatigued

3. □ Moderately fatigued

4. □ Very fatigued

8. How has your appetite been over the past 3 days?

1. □ Very good appetite

2. □ Moderate appetite

3. □ Poor appetite

4. □ No appetite

9. How would you describe your sensation of well-being over the past 3 days?

1. □ Very good sensation of well-being

2. □ Moderately good sensation of well-being

3. □ Not very good sensation of well-being

4. □ Poor sensation of well-being

10. How short of breath have you been over the past 3 days?

1. □ No shortness of breath

2. □ Mild shortness of breath

3. □ Moderate shortness of breath

4. □ Very short of breath

11. How has your physical discomfort been over the past 3 days?

1. □ No physical discomfort

2. □ Mild physical discomfort

3. □ Moderate physical discomfort

4. □ Severe physical discomfort

The Memorial Symptom Assessment Scale8 characterizes 32 physical and psychological symptoms in terms of intensity and frequency, as well as the level of distress from the symptoms [see Table 2]; it is valid for palliative care patients with or without cancer.9 Although the Memorial Symptom Assessment Scale provides a greater range of information than the Edmonton Symptom Assessment Scale, the former is correspondingly more time consuming to use.

Table 2 Memorial Symptom Assessment Scale16

For physical symptoms, patients are instructed to check off all symptoms experienced during the past week and the degree to which the symptom bothered or distressed them. Categories and scores are as follows: Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), and Very much (4). Patients may also add symptoms not listed and rate them on the same scale. For psychological symptoms, patients are instructed to check off all symptoms experienced during the past week and how often each occurred. Categories and scores are as follows: Rarely (1), Occasionally (2), Frequently (3), and Almost constantly (4). Patients may also add symptoms not listed and rate them on the same scale.

Physical Symptom

Severity

0

1

2

3

4

Difficulty concentrating

 

 

 

 

 

Pain

 

 

 

 

 

Lack of energy

 

 

 

 

 

Cough

 

 

 

 

 

Changes in skin

 

 

 

 

 

Dry mouth

 

 

 

 

 

Nausea

 

 

 

 

 

Feeling drowsy

 

 

 

 

 

Numbness or tingling in hands and feet

 

 

 

 

 

Hair loss

 

 

 

 

 

Constipation

 

 

 

 

 

Swelling of arms or legs

 

 

 

 

 

Psychological Symptom

Frequency

0

1

2

3

4

Feeling sad

 

 

 

 

 

Worrying

 

 

 

 

 

Feeling irritable

 

 

 

 

 

Feeling nervous

 

 

 

 

 

Physical Symptoms

PAIN

Diagnosis

Management of pain begins with a careful and detailed assessment [see 11:XIV Pain]. The goal of this assessment is to determine the location and character of the pain, define its cause (or causes), and develop a plan of care.

Pain cannot be measured objectively, and several studies have shown that medical care providers' estimates of patients' pain severity are significantly lower than the patients' self-reports.10,11 Pain is independent of age, gender, marital status, physical function, and cognitive function.12 Therefore, the central guiding principle of pain assessment is to ask the patient and believe the patient's description of pain.

Pain assessment in the elderly is often complicated by coexistent cognitive impairment. The cognitively impaired patient may be unable to express pain adequately or request analgesics and, therefore, is at increased risk for undertreatment of pain.13,14 As with cognitively intact patients, the first step in the assessment of pain in demented patients is to ask them about their pain. Although patients with severe dementia may be incapable of communicating, many patients with mild or moderate impairment can accurately localize and grade the severity of their pain,15 and these self-reports should be regarded as valid.

Untreated pain can result in agitation and disruptive behavior, and it may worsen or precipitate delirium, particularly in cognitively impaired patients.16,17 When delirium prevents communication with the patient, the physician may have to infer that pain is present and proceed with treatment.

Treatment

Opioids are the standard choice for treating pain in terminally ill patients. The physician who provides palliative care needs to have the confidence and competence to prescribe opioids at whatever dose is needed to control pain, as well as the skill to determine when adjuvant analgesics (e.g., antidepressant or antiseizure medication) are needed to manage certain types of pain.18,19 Terminally ill patients are a special population, often suffering chronic pain and taking pain medications over longer periods and at higher dosages.20 Indeed, tolerance to opioids may require that these agents be used in amounts that would be fatal to the opioid-naive patient.

In a multisite study of terminally ill patients in the United States, Weiss and colleagues21 found that half of terminally ill patients experienced moderate to severe pain but that less than one third wanted additional pain treatment from their primary care physician. Reasons for not wanting additional therapy included dislike of analgesic side effects and not wanting to take more pills or injections. Some patients, however, mentioned fear of addiction. This is a common—and unwarranted—concern not only of patients but of some medical personnel, as well.

Several strategies can be used to improve pain relief when opioids are insufficiently effective or cause significant side effects. Adding the nonsteroidal anti-inflammatory drug ketorolac (60 mg orally three times a day) may reduce opioid requirements and opioid-related constipation, although at the price of greater gastric discomfort.22 Use of implantable systems that deliver drugs intrathecally can provide better pain control (i.e., less escalation of pain medication at week 1), less toxicity (i.e., fatigue and depressed level of consciousness), and even improved survival at 6 months.23 Nerve blocks (e.g., celiac plexus block for patients with terminal pancreatic cancer24) can be effective in selected patients with regional pain. Relaxation techniques may be useful adjuncts to other forms of analgesia.25

In patients who are still ambulatory, pain control can be enhanced by having the patient keep a daily pain diary. Nursing interventions (i.e., clinical reassessment and dose adjustment) can be made on the basis of diary entries that indicate fluctuation in pain levels.26

As the goals of care change in the course of a life-threatening illness, higher dosages of pain medication may be needed to achieve comfort. In the last days of life, relief of suffering may require sedation to the point of unconsciousness, a technique referred to as palliative sedation (see below).

RESPIRATORY SYMPTOMS

Dyspnea

Shortness of breath has been described in 70% of cancer patients during the last 6 weeks of life and in 50% to 70% of patients dying of other illnesses.27,28,29 Like pain, dyspnea is a subjective symptom that may not correlate with any objective signs of respiratory compromise,30 and hence, its management can be challenging.

It is important to diagnose and treat any underlying reversible causes of dyspnea. For example, dyspnea caused by congestive heart failure will require diuretics and possibly inotropic support [see 1:II Heart Failure].

When therapy specific to the underlying cause is unavailable or ineffective, several techniques may alleviate breathlessness. Simple measures include pursed-lip breathing and diaphragmatic breathing, leaning forward with arms on a table, cool-air ventilation (from a fan or an open window), and nasal oxygen.

Opioids are highly effective in the amelioration of dyspnea.31,32,33,34 In one study, morphine in doses sufficient to relieve dyspnea had no measurable adverse effect on respiratory rate or effort, oxygen saturation, and carbon dioxide concentration.31 Therefore, morphine is the drug of choice for treating dyspnea in terminal illness.

Lorazepam and other benzodiazepines are also widely used, especially in terminally ill patients whose dyspnea has an anxiety component, although evidence to support this practice is limited.35 In addition, steroids and oxygen therapy may be of benefit [see Table 3]. Although oxygen therapy may alleviate dyspnea and improve quality of life, only limited evidence of its efficacy is available; therefore, oxygen therapy should be prescribed on the basis of patient report of benefit.36

Table 3 Drug Treatment for Dyspnea44

Drug (Trade Name)

Dosage

Comment

Oral morphine

2.5–5 mg p.o., q. 4 hr while awake

Doses for opiate-naive patients

I.V. morphine

0.5 mg/hr; titrate to relief

Once dose requirement established, switch to long-acting oral opiate or fentanyl patch

Nebulized morphine

2.5–10 mg injectable in 2 ml NS

Nebulized hydromorphone

0.25–1 mg injectable in 2 ml NS

Nebulized albuterol

0.083% (3 ml)

Possible adjunct to opioid

Nebulized methylprednisolone (Solu-Medrol)

10 mg

Possible adjunct to opioid

Dexamethasone

Day 1: 16 mg p.o.; days 2–3: 8 mg b.i.d.; days 3–4: 4 mg b.i.d.; subsequent: 2 mg b.i.d.

Possible adjunct to opioid

Prednisone

40 mg b.i.d. for 5–7 days

Possible adjunct to opioid

Lorazepam (Ativan)

1–10 mg/day in two or three divided doses; usual dose, 2–6 mg/day in divided doses. Elderly: 0.5–4 mg/day

For patients whose dyspnea has an anxiety component

Oxygen

2 L/min by nasal cannula; titrate to relief

NS—normal saline

Cough

Cough can be an annoyance or can develop into a major source of suffering by causing muscle strain and increasing fatigue and by interrupting sleep. In one study of lung cancer patients, cough was the most common symptom, affecting 80% of patients until just before death.37 Because the causes of cough are varied, the optimal approach is treatment of the underlying problem, if possible. When such treatment is not possible, however, a productive cough may improve with chest physiotherapy, oxygen, humidity, and suctioning [see Figure 1].38 Antibiotics for infection, N-acetylcysteine, bronchodilators, and guaifenesin are also effective.39,40 Opioids, antihistamines, and anticholinergics decrease mucus production, which can decrease the stimulus for cough. Cough suppressants can be harmful if used in patients with productive cough by causing mucus retention,39,40 which may lead to the formation of mucous plugs and airway obstruction. A patient with a nonproductive cough may benefit from a cough-suppressing agent such as a local anesthetic (e.g., nebulized bupivacaine), bronchodilators, opioids, or a soothing agent such as a lozenge. Benzonatate, steroids, and opiates are effective treatments. Opioids act centrally and are one of the most effective agents against cough.41 Nonopioid antitussives, such as dextromethorphan, may work synergistically with opiates.40

 

Figure 1. Shown are the drug treatments for productive cough and nonproductive cough.38

GASTROINTESTINAL SYMPTOMS

Anorexia, nausea and vomiting, constipation, bowel obstruction, and diarrhea are common and potentially devastating in terminal illness.

Anorexia

Anorexia is nearly universal in patients with a terminal illness.42 Evaluation of anorexia should be concentrated on finding a reversible or treatable cause. It is important to note that cognitive impairment, which is also highly prevalent in advanced disease, may cause a person to be misdiagnosed as anorexic, because the person may be unable to obtain, prepare, or eat meals.43 Often in terminal disease, however, the patient simply loses the desire to eat.

Patients themselves may complain of anorexia because they find the resulting cachexia unacceptable. In such cases, the decision whether to treat is straightforward. Anorexia, however, can often be of more concern to family, friends, and medical staff than to patients themselves. The family may be concerned because loss of appetite is seen as a certain sign of impending death.44 Concern about anorexia may also be rooted in the emotional and psychological meanings that surround food and its consumption: not feeding the patient may be considered equivalent to not caring about the patient. The family should be reassured that anorexia in terminal disease is usually not associated with suffering45; especially at the end of life, patients rarely feel hunger or thirst, and many patients who stop eating experience analgesia and even euphoria. Excessive proteins and lipids can induce nausea and vomiting, and excessive hydration can result in edema and dyspnea.46In the early stages of terminal illness, however, studies have shown that the treatment of anorexia with appetite stimulants may improve patients' quality of life.47,48 Treatment can begin with simple measures. The patient should be encouraged to eat without any restrictions on sugar, salt, or fats, when possible. Alcohol has appetite-stimulating properties, so patients may wish to consider a cocktail or glass of wine before the evening meal.49

Appetite stimulants with proven efficacy in palliative care include dexamethasone, in dosages of 2 to 20 mg/day (recommended because its long half-life permits once-daily dosing and because it has minimal mineralocorticoid effects) and megestrol acetate (beginning with 200 mg every 8 hours and titrating to 800 mg/day).50 In addition, dronabinol is approved for the treatment of anorexia associated with weight loss in patients with AIDS (starting with 2.5 mg twice daily, before lunch and supper, and titrating to effect and tolerability).

Anorexia in patients with dementia

Many patients with Alzheimer disease progress to a stage at which they are unable to eat on their own or even chew and swallow reliably. Before agreeing to gastrostomy tube placement for such patients, family members must be made aware of the many complications of tube feeding, such as repeated infections. The needle sticks, transfer to a hospital, and restraints that such infections require are especially burdensome for a confused patient who cannot understand the reason for such interventions.51 In addition, patients with advanced neurologic impairment are at high risk for pneumonia from a variety of causes, including but not limited to aspiration. There is no evidence that tube feeding reduces the risk of pneumonia in such patients; it may even increase the risk.52 One study of hospitalized patients with advanced dementia found that insertion of a feeding tube had no measurable influence on survival; regardless of feeding tube placement, median mortality was 50% at 6 months.53 Nevertheless, placement of a feeding tube was very common in the study, especially in patients who were African American or who had previously lived in a nursing home.

Of note, forgoing artificial nutrition and hydration does not seem to result in high levels of discomfort for patients with severe dementia who have mostly or completely stopped eating or drinking.54 Because of the terminal and irreversible nature of end-stage dementia and the substantial burden that continued artificial nutrition and hydration may pose for these patients, they are better served by palliative care that focuses predominantly on their comfort. Comfort care is viewed as preferable to life-prolonging measures by a substantial proportion of nursing home patients and family members.55 Families should be reassured that it is never unethical to forgo artificial nutrition and hydration if these interventions are unlikely to help the patient.

Nausea and Vomiting

Nausea and vomiting occur in up to 62% of patients with terminal cancer56 and 27% of patients dying of other causes. There are multiple potential causes for both nausea and vomiting [see Table 4].49 Once the cause has been determined, symptomatic relief is relatively easy to achieve with the appropriate medications [see Table 5].38 The anatomic sites most involved in the physiology of nausea are the gastric lining, the chemoreceptor trigger zone in the base of the fourth ventricle, the vestibular apparatus, and the cortex. Stimulation of the vomiting center in the brain from one or more of these areas is mediated through the neurotransmitters acetylcholine and histamine. Serotonin and dopamine are important neurotransmitters in the gastric lining and the chemoreceptor trigger zone; acetylcholine acts in the vestibular apparatus. Cortical responses are mediated via both neurotransmitters and learned responses (e.g., nausea related to anxiety or anticipatory nausea with chemotherapy).57

Table 4 Management of Nausea and Vomiting38

Etiology

Pathophysiology

Therapy

Mechanical obstruction—intraluminal

Constipation, obstipation

Laxatives; disimpaction

Mechanical obstruction—extraluminal

Tumor, fibrotic stricture

Surgery, fluid management, steroids, octreotide, scopolamine

Medications—chemotherapy

Chemoreceptor trigger zone, GI tract

Antiserotonin, antidopamine, steroids

Medications—NSAIDs

GI tract irritation

Cytoprotective agents, antacids

Medications—opioids

Chemoreceptor trigger zone, vestibular effect, GI tract

Antidopamine, anticholinergic, prokinetic agents, stimulant cathartics

Medications—other

Chemoreceptors

Antidopamine, antihistamine

Meningeal irritation

Increased intracranial pressure

Steroids

Mentation (e.g., anxiety)

Cortical

Anxiolytics

Metabolic—hypercalcemia

Chemoreceptor trigger zone

Antidopamine, antihistamine

Metabolic—hyponatremia

Chemoreceptor trigger zone

Antidopamine, antihistamine

Metabolic—hepatic/renal failure

Chemoreceptor trigger zone

Rehydration, steroids

Metastases—cerebral

Increased intracranial pressure

Steroids, mannitol

Chemoreceptor trigger zone

Antidopamine, antihistamine

Metastases—liver

Toxin buildup

Antidopamine, antihistamine

Microbes—gastroenteritis

GI tract

Anti-infectives, antacids

Microbes—sepsis

Chemoreceptor trigger zone

Antidopamine, antihistamine, anti-infectives

Movement

Vestibular stimulation

Anticholinergic

Mucosal irritation

GI hyperacidity, GERD

Cytoprotective agents, antacids

Myocardial—ischemia, CHF

Vagal stimulation, cortical, chemoreceptor trigger zone

Oxygen, opioids, antidopamine, antihistamine, anxiolytics

CHF—congestive heart failure  GERD—gastroesophageal reflux disease  NSAIDs—nonsteroidal anti-inflammatory drugs

Table 5 Medications for Nausea and Vomiting28

Administration

Category

Drug (Trade Name)

Dosage

Oral

Corticosteroid

Dexamethasone

2–8 mg q. 6–12 hr

Antidopamine

Haloperidol (Haldol)

0.5–5 mg q. 6–8 hr

Prochlorperazine (Compazine)

5–10 mg q. 4–6 hr

Prochlorperazine SR

10–15 mg b.i.d.

Antihistamine

Diphenhydramine (Benadryl)

25–50 mg q. 4–6 hr

Hydroxyzine (Atarax)

25–50 mg t.i.d.-q.i.d.

Promethazine (Phenergan)

12.5–25 mg t.i.d.-q.i.d.

Anticholinergic

Hyoscyamine (Levsin)

0.125–0.25 S.L. q. 4 hr

Meclizine (Antivert)

12.5–25 mg b.i.d.-q.i.d.

Anxiolytic

Lorazepam (Ativan)

1–2 mg q. 2–4 hr

Prokinetic

Metoclopramide (Reglan)

10–40 mg q.i.d.

Antiserotonin

Ondansetron (Zofran)

8 mg p.o., t.i.d.-q.i.d.

Other

Dronabinol (Marinol)

2.5–10 mg b.i.d., t.i.d.

Thiethylperazine (Torecan)

10 mg q.d.-t.i.d.

Trimethobenzamide (Tigan)

250 mg t.i.d.-q.i.d.

Rectal suppositories

Antidopamine

Prochlorperazine (Compazine)

25 mg q. 6 hr

Antihistamine

Promethazine (Phenergan)

12.5, 25, 50 mg t.i.d.-q.i.d.

Other

Trimethobenzamide (Tigan)

200 mg t.i.d.-q.i.d.

Continuous intravenous infusion

Corticosteroids

Dexamethasone

8–100 mg/24 hr

Antidopamine

Haloperidol (Haldol)

2.5–10 mg/24 hr

Anticholinergic

Hyoscyamine (Levsin)

1–2 mg/24 hr

Scopolamine

0.8–20 mg/24 hr

Antiserotonin

Odansetron (Zofran)

0.45 mg/kg/24 hr

Prokinetic

Metoclopramide (Reglan)

20–80 mg/24 hr

Intermittent intravenous infusion

Corticosteroids

Dexamethasone

2–8 mg q. 4–6 hr

Antidopamine

Haloperidol (Haldol)

0.5–2 mg q. 4–6 hr

Prochlorperazine (Compazine)

5–10 mg q. 4–6 hr

Antihistamine

Diphenydramine (Benadryl)

25–50 mg q. 6 hr

Anxiolytic

Lorazepam (Ativan)

1–2 mg q. 6–8 hr

Prokinetic

Metoclopramide (Reglan)

10–20 mg q. 6 hr

Antiserotonin

Ondansetron (Zofran)

4–8 mg q. 8 hr

Granisetron (Kytril)

10 µg/kg q.d.

Other

Dronabinol (Marinol)

5 mg/m2 q. 4 hr (maximum, six doses/day)

The major causes of nausea and vomiting can be classified by the mechanisms' principal site of action. Dopamine-mediated nausea is probably the most common form of nausea and the most frequently targeted one for initial symptom management. Antidopamine medications are phenothiazines and butyrophenone neuroleptics (metoclopramide and prochlorperazine). They may cause drowsiness and extrapyramidal symptoms. Haloperidol is a highly effective antinausea agent and may be less sedating. Antihistamines such as diphenhydramine can be used to control nausea, but they may cause sedation. Antihistamines also have anticholinergic properties. Serotonin has been implicated in chemotherapy-associated nausea. Antiserotonin medications (e.g., odansetron) can be effective, but they are expensive.

Nausea can also result from slow gastric and intestinal motility; so-called squashed stomach syndrome from mechanical compression of the stomach; and constipation. Hence, prokinetic agents (e.g., metoclopramide) and aggressive fecal disimpaction and institution of a bowel regimen (see below) should be considered as therapeutic modalities. In some patients, hyperacidity and mucosal erosion may also be associated with significant nausea. In these patients, one should consider the use of ant-acids, histamine2 blockers, proton-pump inhibitors, and misoprostol [see 4:XIV Gastrointestinal Motility Disorders].

Constipation

Constipation can lead to serious complications, such as bowel obstruction, ulceration, or perforation, as well as delirium. Because constipation is so common in terminal illness, appropriate management includes the institution of preventive measures in patients at high risk for this complication.

Diagnosis

Assessment of constipation begins with inquiry about the frequency and consistency of stools; possible contributing factors, such as medications, reduced mobility, and a low-fiber diet; and any accompanying symptoms that suggest complications, such as nausea, vomiting, abdominal pain, distention, and discomfort.58 As with any symptom, the search for a reversible cause is primary. A plain x-ray can be useful to evaluate for ileus or bowel obstruction. Invasive evaluation with colonoscopy should be considered in difficult, refractory, or complicated cases.

Many medications can contribute to constipation. These include beta blockers, calcium channel blockers, anticholinergic agents, and diuretics.58,59 First and foremost, however, are opioid analgesics: constipation is a universal side effect of opioid therapy, especially in the terminally ill. For that reason, every terminally ill patient who is placed on opioids should also be started on a preventive regimen for constipation. The bowel regimen in these patients starts with stool softeners and stimulant laxatives and progresses through hyperosmotic agents and enemas, as necessary [see Table 6].60 This regimen can also be utilized for treatment of constipation from other causes, once intestinal obstruction is ruled out.

Table 6 A Progressive Bowel Regimen for Patients Receiving Opioid Therapy60*

Step 1    Docusate, 100 mg b.i.d.
   Senna, 1 tablet q.d. or b.i.d.
Step 2
   Docusate, 100 mg b.i.d.
   Senna, 2 tablets b.i.d.
   Bisacodyl rectal suppositories, 1–2 after breakfast
Step 3
   Docusate, 100 mg b.i.d.
   Senna, 3 tablets b.i.d.
   Bisacodyl rectal suppositories, 3–4 after breakfast
Step 4
   Docusate, 100 mg b.i.d.
   Senna, 4 tablets b.i.d.
   Lactulose or sorbitol, 15 ml b.i.d.
   Bisacodyl suppositories, 3–4 after breakfast
Step 5
   Sodium phosphate or oil-retention enema; if no results, add a high-colonic tap-water enema
Step 6
   Docusate, 100 mg b.i.d.
   Senna, 4 tablets b.i.d.
   Lactulose or sorbitol, 30 ml b.i.d.
   Bisacodyl rectal suppositories, 3–4 after breakfast
Step 7
   Docusate, 100 mg b.i.d.
   Senna, 4 tablets b.i.d.
   Lactulose or sorbitol, 30 ml q.i.d.
   Bisacodyl rectal suppositories, 3–4 after breakfast

*The bowel regimen is started at the time of or before the initiation of opioid therapy, and it should be continued for the duration of opioid therapy. The clinician should start with step 1 and progress through higher steps until an effective regimen is found.

Treatment

Treatment of constipation is with oral agents or rectal suppositories and can focus on softening the stool, enlarging stool volume, or promoting bowel peristalsis. Laxative categories include detergents, stimulants, osmotic agents, prokinetic agents, lubricant stimulants, and large-volume enemas [see Table 7]. Polyethylene glycol solution (GoLYTELY) or powder (MiraLax) is an osmotic agent that is marketed as a bowel cleanser to prepare patients for colonoscopy, but it is often effective in relieving constipation and may cause less cramping than other laxatives. Whichever laxative is chosen, the clinician should prescribe the maximum therapeutic dose of the agent before switching to another one.

Table 7 Treatments for Constipation

Laxative type

Mechanism

Agent

Dosage

Comment

Stimulant

Irritate the bowel and increase peristaltic activity

Prune juice

120–240 ml q.d. or b.i.d.

 

Senna

1–2 tablets p.o., q.h.s.

Titrate to effect; ≤ 8 tablets b.i.d.

Bisacodyl

10–15 mg p.o., h.s.; or 10 mg p.r., after breakfast

Titrate to effect

Osmotic

Draw water into the bowel lumen, increase overall stool volume

Lactulose

30 ml p.o., q. 4–6 hr

Titrate to effect

Sorbitol, 70% solution

2 ml/kg, up to 50 ml p.o., q.d.-t.i.d.

 

Milk of Magnesia

1–2 tbsp, q.d.-t.i.d.

 

Magnesium citrate

1–2 bottles p.r.n.

 

Polyethylene glycol solution

1–4 L p.o.

Drink 8 oz q. 10 min until consumed

Polyethylene glycol powder

17 g (1 tbsp) powder in 8 oz water, q.d.

2–4 days may be required to produce a bowel movement; increase dose as needed

Detergent (stool softeners)

Increase water content in stool by facilitating the dissolution of fat

Docusate sodium

1–2 capsules p.o., q.d.-b.i.d.

Titrate to effect

Docusate calcium*

1–2 capsules p.o., q.d.-b.i.d.

Titrate to effect

Prokinetic agents

Stimulate the bowel's myenteric plexus, and increase peristaltic activity and stool movement

Metoclopramide

10–20 mg p.o., q. 6 hr

 

Lubricant stimulants

Lubricate the stool and irritate the bowel, increasing peristaltic activity and stool movement

Glycerin suppositories

Daily

 

Mineral oil or peanut oil enema

Daily

 

Large-volume enemas

Soften stool by increasing its water content; distend the colon and induce peristalsis

Warm-water enema

Daily

Addition of soapsuds irritates bowel wall to induce peristalsis

High-colonic enemas

Utilize gravity to bring fluid to more proximal parts of bowel

2 L of water or saline warmed to body temperature, hung on I.V. pole at ceiling level

Run in over 30 min, repeat q. 1 hr

 

*Not available in the United States.

Fecal impaction

Although impaction of stool in the rectum is a complication of constipation, the typical clinical manifestation is so-called overflow diarrhea from leakage of unformed stool around the obstruction. A digital rectal examination may confirm fecal impaction in the distal rectum, but abdominal x-rays may be required for the diagnosis of more proximal impaction. Treatment of fecal impaction is from below, utilizing digital disimpaction and rectal laxatives (suppositories, enemas, or both); only if those fail should oral treatment be attempted.58

Bowel Obstruction

The prevalence of bowel obstruction is as high as 40% in bowel and pelvic cancers.61 Constipation and fecal impaction are the most common causes of bowel obstruction in terminal illness. Symptoms of bowel obstruction include anorexia, confusion, nausea and vomiting, constipation, and pain. Diagnosis is made on the basis of the clinical presentation and abdominal x-rays.

Consultation with a surgeon is advisable to establish a treatment plan. In addition to aggressive measures to prevent or treat constipation and fecal impaction (see above), treatment of bowel obstruction may involve endoscopic decompression,62 insertion of a self-expandable metal stent,63 surgical relief of obstruction, nasogastric suction, and pharmacologic measures. Colicky or cramping pain may respond to dicyclomine, opioids (parenteral or rectal), and warm soaks to the abdomen. The obstruction and associated nausea and vomiting may respond to metoclopramide, haloperidol, or dexamethasone. Parenteral octreotide is also useful in this setting to decrease the volume of bowel secretions.

Diarrhea

Diarrhea, which is often secondary to fecal impaction or antibiotic-associated colitis, is a particularly distressing and exhausting symptom in the terminally ill patient.58 Once impaction, overgrowth, and other causes (e.g., gastrointestinal bleeding, malabsorption, and medications) have been ruled out, kaolin-pectin, psyllium, loperamide, or tincture of opium may be tried. Octreotide (see above) is an effective means of reducing gastrointestinal secretions.

MOUTH SYMPTOMS

Oral problems can cause altered taste, pain, and difficulty swallowing, which may lead to reduced food and fluid intake. Good hydration, hygiene, and regular observation can keep oral problems to a minimum. The patient's teeth should be brushed twice daily with toothpaste. Daily observation of the oral mucosa is recommended.

Dentures also require regular cleansing. Dentures may cease to fit properly in patients who lose a significant amount of weight. Some of those patients may wish to have their dentures refitted; others (especially those nearing death) will choose to forgo this arduous process.

Key questions to ask regarding the mouth [see Table 8] include the following: Is the mouth dry? Is infection present? Is the mouth dirty? Is the mouth painful? Are oral ulcerations present?64

Table 8 Local Measures for Oral Problems64

Dry mouth
   Semifrozen fruit juice
   Frequent sips of cold water or water sprays
   Petroleum jelly rubbed on lips
Dirty mouth
   Regular brushing with soft toothbrush and toothpaste
   Pineapple chunks
   Cider and soda mouthwash
Infected mouth
   Tetracycline mouthwash, 250 mg every 8 hr (one capsule dissolved in 5 ml water)
Painful mouth
   Topical corticosteroids: betamethasone, 0.5 mg in 5 ml water, as mouthwash; or triamcinolone in carmellose paste
   Coating agents: sucralfate suspension as mouthwash, carmellose paste, carbenoxolone
   Topical anesthesia: benzocaine or lozenges containing local anesthetics

Dry Mouth

The presence of saliva is usually taken for granted, but the lack of it can seriously damage the quality of life. Xerostomia (the subjective sensation of dry mouth) may result from salivary gland disease or systemic conditions such as Sjögren syndrome, Parkinson disease, AIDS, or diabetes65; it may also be a side effect of medications, including agents with anticholinergic action, benzodiazepines, diuretics, and interleukin-2.66 Regardless of the cause, xerostomia almost always requires symptomatic treatment. The goal of therapy is to moisten the oral mucosa, and the best, simplest way is for the patient to sip water frequently. However, mouth moisteners and artificial salivas exist and may be preferred by some patients.64,66 Pilocarpine tablets may be used, at a dosage of 5 to 10 mg every 8 hours, if the above measures fail. Side effects may include nausea, diarrhea, urinary frequency, and dizziness. Other nonpharmacologic treatments include eating ice chips and sucking on hard candy.

Oral Ulcers/Mucositis

Oral infection can have multiple causes. Aphthous ulcers are common and can be eased by topical corticosteroids, tetracycline mouthwash, or thalidomide. Oral candidiasis usually presents as adherent white plaques but can also present as erythema or angular cheilitis. Nystatin suspension is the usual treatment, but a 5-day course of oral ketoconazole, 200 mg daily, can also be used. Severe viral infection (herpes simplex or zoster) requires treatment with acyclovir, 200 mg every 4 hours for 5 days. Malignant ulcers are often associated with anaerobic bacteria and may respond to metronidazole, 400 to 500 mg orally or rectally every 12 hours or as a topical gel.64

SKIN SYMPTOMS

Pressure Ulcers

Pressure ulcers typically result from both intrinsic and extrinsic factors [see Table 9]. Major sites of pressure ulcers in terminally ill patients include the ear and the skin overlying the spine (apex of kyphosis), sacrum, greater femoral trochanter, head of the fibula, and malleolus. Prevention should emphasize these sites and should include daily visual inspection of them in patients at risk for pressure sores.

Table 9 Risk Factors for Pressure Ulcers

Intrinsic

Extrinsic

Malnutrition
   Protein
   Vitamin C
   Zinc
Diminished mobility
Tissue fragility
Anemia
Dehydration
Hypotension
Poor peripheral perfusion
Incontinence
Neurologic deficit
   Sensory
   Motor
Older age
Coma
Moribund state

Pressure
   Shear
   Trauma
   Friction
Crumpled bedclothes
Restraints
Bed rails
Poor hygiene
Hospital equipment
Oxygen tubing
Heart monitor wires

Prevention and treatment of pressure sores require targeting risk factors and minimizing them.67 Caregivers need to minimize pressure by turning and repositioning the patient frequently and avoiding shear (sliding movement) and friction. They should be aware that even crumpled bedclothes can impair circulation. How a patient moves or is moved by caregivers needs to be assessed and monitored. Even with regular turning and careful lifting and positioning, special pressure surfaces or mattresses are sometimes needed.64 Fragile skin that is at risk for breakdown should be covered with clear, occlusive dressings; pressure points should be covered with thin, hydrocolloid dressings.

Caregivers must keep the patient's skin clean and dry. Absorbent surfaces, urinary catheters, and rectal tubes may be helpful, but they must be used carefully because of their attendant complications.49

Nutrition is an important factor in both prevention and treatment. Good hydration, a diet that is high in protein and carbohydrates, and vitamin C supplements help maintain skin integrity and encourage healing.

If pressure ulcers develop, they should be covered with gel or colloid dressings, which keep the area moist, reduce pain, and can be left in place for several days. The pain of dressing changes can be eased by extra analgesia before each change.64 The clinician should instruct caretakers to give oral pain medication one-half hour before the dressing change. The dose is determined by whether or not the patient is on regular opioid medications. If the patient is not on regular pain medications, start with 15 mg of immediate-release morphine. If the patient is on a regular opioid regimen, the predressing dose should be the same as the rescue dose.

Pressure ulcer management needs to be consistent with the overall goals of care. If maintenance or improvement of function is the goal and the patient's life expectancy is weeks to months, the ulcer should be treated according to the usual management guidelines. If life expectancy is very limited (e.g., days), the intent should be to optimize quality of life and minimize pain and discomfort (such as from excessive dressing changes or debridement).

Malignant Ulcers

For uncomplicated malignant ulcers, pain relief and wound care are managed in the same way as pressure ulcers. Malignant wounds can present special problems, however, which may include bleeding, exudate, infection, odor, and disfigurement. A bleeding malignant ulcer should be treated with radiation therapy, topical sucralfate, or topical tranexamic acid. Dirty ulcers should be debrided, which can be accomplished chemically. Altered body image from disfiguring wounds can be lessened with cavity foam dressings. Furthermore, empathetic listening is often therapeutic in itself. Anxiety, anger, or depression needs specific support, however64 [see CE:XI Management of Psychosocial Issues in Terminal Illness].

Foul-Smelling Wounds

Odors from wounds may be very distressing to patients, families, and caregivers and may lead to poor quality of care, as even professional caregivers tend to avoid sickening smells. Wound odors are usually the result of anaerobic infections or poor hygiene. Treat superficial infections with topical metronidazole or silver sulfadiazine. These agents are expensive, however; if a less costly alternative is required, a diluted hydrogen peroxide solution can be used.49 For soft tissue infections, systemic metronidazole can be added to topical management.

To control odors, caregivers can place a pan containing kitty litter or activated charcoal under the patient's bed, provide adequate room ventilation, place an open cup of vinegar in the room, or burn a candle. Special charcoal-impregnated dressings placed over the odorous wound may also be helpful.49

Psychiatric Symptoms

Adjustment disorders, depression, anxiety, dementia, and delirium are the most common psychiatric problems encountered in dying patients.68,69 Depending on the severity of the psychiatric problems, their management may be within the capacity of the primary care physician or may require referral [see CE:XI Management of Psychosocial Issues in Terminal Illness].

DELIRIUM

Delirium occurs in 28% to 83% of terminally ill patients.70 Symptoms of delirium include inability to maintain attention, waxing and waning of consciousness, psychomotor changes, disturbance of sleep-wake cycle, disorientation, visual or auditory hallucinations, and problems with memory and language.71 Other terms often used synonymously with delirium include acute confusional state, metabolic encephalopathy, and sundowning. In contrast to dementia, delirium is more rapid in onset (developing over hours to days), fluctuates in severity, is potentially reversible, and is associated with a lesser degree of memory impairment.

Delirium is a multifactorial syndrome, involving preexisting risk factors and precipitating factors that occur during hospitalization. Factors that predispose a patient to delirium include vision impairment, severe illness, cognitive impairment, and dehydration.72 In older patients, cognitive impairment that is so mild as to be inapparent when such patients are well may nevertheless increase the risk of delirium. Precipitating factors include the use of physical restraints, malnutrition, taking more than three drugs, bladder catheter use, and any iatrogenic event.72 Prevention of delirium can be accomplished by targeting risk factors.72

Management of delirium in the terminally ill patient includes correction of the cause and provision of symptomatic relief. In patients with morphine-induced delirium, opioid rotation from morphine to fentanyl may be effective in alleviating the delirium; because fentanyl works through different receptors, the same degree of pain control may be accomplished with lower doses of narcotics.73 Identification and treatment of underlying diseases or conditions are paramount—for example, give antibiotics for sepsis or oxygen for shortness of breath. In patients with underlying dementia, the possibility of untreated pain deserves special consideration. In the past, physicians were taught that the use of narcotic analgesics is dangerous in patients with dementia because those agents cause delirium. That is not true of a demented patient who becomes agitated or belligerent because of pain, however; in those cases, a dose of a narcotic analgesic may calm the patient within an hour or so. One study demonstrated that in patients 85 years of age or older with advanced dementia, treatment with low-dose, long-acting opioids can lessen agitation that is otherwise difficult to control.74 The risk of undertreating severe pain should be of greater concern, both medically and ethically, than the risk of worsening delirium with analgesic medications.

Additional means of treating delirium include minimizing any sensory impairments by providing appropriate eyeglasses or hearing aids and maintaining a quiet, familiar, and reassuring setting. It is important to maintain communication with the patient, using frequent reorientation; familiar objects, places, and people; and avoidance of stimulus overload or deprivation.75

Pharmacologic symptom relief is best achieved with the use of an antipsychotic agent such as haloperidol or risperidone [see Table 10]. Benzodiazepines or sedatives should be used only if antipsychotic agents fail.76

Table 10 Drug Treatment for Agitation or Delirium33

Acute

Haloperidol, 0.5–5 mg p.o., p.r., I.M., I.V., or S.C.; titrate until calm

Chlorpromazine, 1 mg I.V. q. 2 min until calm

Chronic

Haloperidol, 0.5–5 mg p.o. or p.r., b.i.d. (maximum dose, 100 mg/day)

Thioridazine, 10–25 mg p.o., b.i.d. (maximum dose, 800 mg/day)

Risperidone, 0.5 mg p.o., b.i.d.; increase by 0.5 mg b.i.d. q. 24 hr (maximum dose, 6 mg/day)

Chlorpromazine, 10–50 mg p.o. or p.r., b.i.d. (maximum dose, 500 mg/day)

Olanzepine, 2.5–15 mg p.o., q.d.

Terminal Delirium

Delirium may be an irreversible part of the dying process. Many terminally ill patients have escalating restlessness, agitation, or hallucinations that can be relieved only with sedation.77 When death is imminent, reversing the underlying causes of delirium is not possible. Instead, the clinician should focus on the management of the symptoms associated with the terminal delirium and bring comfort to the patient and family.

Benzodiazepines are widely used in the management of terminal delirium because they are anxiolytics, amnestics, skeletal muscle relaxants, and antiepileptics. Oral lorazepam (1 to 2 mg as an elixir, or the tablet predissolved in 0.5 to 1.0 ml of water and administered against the buccal mucosa) should be given every hour as needed; it will settle most patients at a daily dose of 2 to 10 mg. The lorazepam can then be given in divided doses, every 3 to 4 hours, to keep the patient settled. For a few extremely agitated patients, high doses of lorazepa—20 to 50 mg or more per 24 hours—may be required. A midazolam infusion (1 to 5 mg S.C. or I.V. every 1 hour, preceded by repeated loading boluses of 0.5 mg every 15 minutes to effect) may be a rapidly effective alternative.49

Palliative sedation

When terminal delirium cannot be adequately controlled despite aggressive efforts to identify a tolerable therapy that does not compromise consciousness, it may be necessary to resort to palliative sedation. Most physicians define palliative sedation as the act of purposely inducing and maintaining a pharmacologically sedated and unconscious state, without the intent to cause death. A Japanese study of palliative sedation therapy in terminally ill cancer patients found that the technique is usually effective and safe, but that fatal complications related to sedation occur in a small number of patients.78

Palliative sedation is usually accomplished with benzodiazepines, neuroleptics, or barbiturates. Propofol may be useful for patients in whom traditional sedating agents have failed, such as patients with intractable nausea and vomiting.79

Once palliative sedation is initiated, the dosage of the sedative agent should not be increased unless the patient awakens or becomes restless, tachypneic, or tachycardic. Increasing the level of sedation in the absence of a clinical indication might imply that the physician is intending to hasten death, which if true would cross the line between palliative sedation and physician-assisted suicide or euthanasia [seeCE:IX Palliative Care].80

Terminal Wean

Mechanical ventilation is often tried in patients with respiratory distress, when there is hope that their condition will improve. This is best referred to as a time-limited trial. If reversal of the acute medical condition proves unsuccessful, the physician needs to discuss discontinuance of ventilation with the family.

Terminal ventilation withdrawal should be approached with attention to ensuring the patient's comfort and to enhancing the family's access to the bedside.81 Miles82 recommends a 10-step protocol, which applies to unconscious patients dependent on a ventilator:

  1. Shut off and remove all monitors and alarms from the patient's room.
  2. Remove equipment that impedes access to the patient's hands (e.g., intravenous lines, pulse oximeter, restraints). Hands are for holding.
  3. Remove encumbering or disfiguring devices from the bedside.
  4. Invite the family to be with the patient.
  5. Quietly and personally request that pressors be turned off and that intravenous infusions be set to keep veins open.
  6. Watch for distressing symptoms, such as agitation, tachy-pnea, or seizures; treat appropriately (e.g., with diazepam) if they appear.
  7. Turn the fraction of inspired oxygen (FIO2) down to 20% and observe the patient for respiratory distress.
  8. If the patient appears comfortable, remove the endotracheal tube with a clean towel in hand.
  9. Educate and debrief the house staff and nursing staff about the process.
  10. Consider contacting the family during the bereavement period, whether by letter or visit.

The goal is for a peaceful, pain-free death for the patient and a supportive, comfortable environment for the family and friends. It is important to warn family that a patient removed from the ventilator may live for hours to days afterward and to reassure them that all measures necessary to ensure comfort during the dying process will be used.

Symptom Management in the Last Hours of Life

The final hours of living can be some of the most important ones for the patient and for family. Managed well, they can lead to a peaceful death and healthy grief and bereavement.49

During the final hours, patients usually need skilled care around the clock. Ideally, the environment will allow family and friends both easy access to their loved one and privacy. All who are present should presume that the unconscious patient hears everything.49

It is important to be knowledgeable about the normal physiologic changes that occur in the last hours of life and to educate the patient's family about them. Reassure the family that dehydration in the final hours of living does not cause distress and may stimulate endorphin release that adds to the patient's sense of well-being. Moaning and groaning, although frequently misinterpreted as pain, is often terminal delirium (see above). Decreased hepatic and renal function lead to the accumulation of metabolites, which may cause terminal delirium. Only essential medications should be used, at appropriate doses as needed.49

In the final hours of life, many persons in semiconscious or unconscious states are unable to swallow saliva reflexively or to cough up mucus. This inability to clear secretions from the oropharynx and trachea results in the so-called death rattle—noisy respiration as the secretions move up and down with expiration and inspiration. The cause and meaning of death rattle should be explained to the family, and an anticholinergic drug should be administered to the patient to reduce pharyngeal secretions (e.g., hyoscine as a single parenteral dose or by continuous infusion, or scopolamine by patch).83 At times, it may be necessary to reposition the patient or to suction the airway gently with a soft catheter. Reassure the family that despite the way the breathing sounds, the patient is not uncomfortable.

The removal of the body too soon after death can be even more upsetting to the family than the moment of death; the family should be allowed time with the body.49 After the patient has died, follow-up with the family is important to ensure that grief and bereavement are progressing normally [see CE:XI Management of Psychosocial Issues in Terminal Illness].

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Editors: Dale, David C.; Federman, Daniel D.