Management of Common Symptoms in Terminally Ill Patients: Part II

END-OF-LIFE CARE

Management of Common Symptoms in Terminally Ill Patients: Part II. Constipation, Delirium and Dyspnea DOUGLAS D. ROSS, M.D., PH.D., and CARLA S. ALEXANDER, M.D. University of Maryland School of Medicine, Baltimore, Maryland

In addition to pain, patients who are approaching the end of life commonly have other symptoms. Unless contraindicated, prophylaxis with a gastrointestinal motility stimulant laxative and a stool softener is appropriate in terminally ill patients who are being given opioids. Patients with low performance status are not candidates for surgical treatment of bowel obstruction. Cramping abdominal pain associated with mechanical bowel obstruction often can be managed with morphine (titrating the dosage for pain) and octreotide. Delirium is common at the end of life and is frequently caused by a combination of medications, dehydration, infections or hypoxia. Haloperidol is the pharmaceuti- cal agent of choice for the management of delirium. Dyspnea, the subjective sensation of uncomfortable breathing, is often treated by titration of an opioid to relieve the symptom; a benzodiazepine is used when anxiety is a component of the breathlessness. (Am Fam Physician 2001;64:1019-26.)

This is part of a series hysical symptoms other than nal motility stimulant laxative and a stool of articles and features pain often contribute to suffering softener, unless use of these agents is con- on issues in end-of-life at the end of life. Part I of this traindicated. A stool softener alone is usually care. Coordinator of this series is Caroline two-part article reviewed the not sufficient to alleviate opioid-induced Wellbery, M.D., assis- management of fatigue, anorexia, constipation. tant deputy editor Pcachexia, nausea and vomiting in patients of AFP. with cancer, acquired immunodeficiency syn- BOWEL OBSTRUCTION drome (AIDS) and other terminal illnesses. Mechanical bowel obstruction occurs in Part II discusses measures to alleviate consti- approximately 3 percent of patients with can- pation, delirium and dyspnea. With appropri- cer who are receiving hospice care.2 It is most ate diagnosis and management, many of these frequently associated with ovarian and colon symptoms can be alleviated in patents who cancers. In terminally ill patients with low are approaching the end of life. performance status, surgical treatment of bowel obstruction is not appropriate because Constipation of high mortality and recurrence rates.2 Constipation is a frequent cause of nausea Cramping abdominal pain associated with and vomiting in terminally ill patients. Man- mechanical bowel obstruction primarily agement depends on assessment and manip- results from the accumulation of secreted ulation of the four major components bowel fluid. This problem can often be man- This is part II of a two- required for normal bowel movements: aged with titration of the morphine dosage to part article on the intestinal solids, water, motility and lubrica- manage pain, along with the administration management of com- 1 mon symptoms in tion (Table 1). of octreotide (Sandostatin), a synthetic terminally ill patients. Constipation resulting from opioids is somatostatin that inhibits the intraluminal Part I, “Fatigue, dose-related, and patients do not develop tol- secretion of intestinal fluid. Anorexia, Cachexia, erance to this side effect. Prophylaxis is cru- Treatment with medications commonly Nausea and Vomiting,” cial because opioid-induced constipation is used to manage nausea and vomiting (e.g., appeared in the Sep- tember 1 issue (Am much easier to prevent than to treat. All haloperidol [Haldol], diphenhydramine Fam Physician 2001; patients for whom opioids are prescribed [Benadryl], octreotide) should also be con- 64:807-14). should be given a prophylactic gastrointesti- sidered. (Use of these drugs is discussed in

SEPTEMBER 15, 2001 / VOLUME 64, NUMBER 6 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1019 All patients for whom opioids are prescribed should be given Delirium a prophylactic gastrointestinal motility stimulant laxative and a Delirium is a disturbance of consciousness and cognition with a sudden onset that may stool softener, unless use of these agents is contraindicated. be accompanied by increased psychomotor activity.3 This symptom occurs in 25 to 85 percent of terminally ill patients.4,5 Mental part I of this two-part article.) The exception status changes can be very distressing to the is the prokinetic agent metoclopramide family, who observe agitation, apparent fear (Reglan), which may worsen symptoms of or what they believe to be uncontrolled pain mechanical obstruction. Stool softeners and in the patient. Delirium often heralds the end osmotic agents may be useful in patients with of life and may require active sedation in up partial mechanical obstruction. to 25 percent of patients.4

TABLE 1 End-of-Life Care: Treatment of Constipation by Manipulation of Factors Affecting Bowel Movements

Factor Etiologic event Correction or treatment Comments

Low intestinal Low-fiber diet Psyllium Caution is advised in patients with solids low fluid intake, as psyllium may cause impaction Low stool water Dehydration, reduced intestinal secretion, Hyperosmolar content slow transit time of stool nonabsorbable agents Magnesium salts Contraindicated in patients with renal failure Phosphorous salts Contraindicated in patients with renal failure Glycerin suppositories Sorbitol (30 mL every 2 Sickly sweet taste; may cause cramps to 4 hours until stool) Lactulose (30 mL orally every 4 to 6 hours) Low Bed-ridden patients; neurodegenerative Senna Stimulates myenteric plexus gastrointestinal disorders; drugs, including morphine, Bisacodyl motility tricyclic antidepressants, scopolamine Prune juice Inexpensive, effective (Transderm Scop), diphenhydramine Casanthranol (Benadryl), vincristine (Oncovin), verapamil (Calan) and other calcium channel blockers, iron, aluminum and calcium salts Poor Dehydration Dioctyl sodium Inadequate alone to counteract gastrointestinal sulfosuccinate opioid-induced constipation lubrication Mineral oil enemas Do not give mineral oil by mouth, as aspiration may cause pneumonitis. Glycerin suppositories

Adapted with permission from Hallenbeck J, Weissman D. Fast fact and concepts #15: Constipation—what makes us go. June, 2000. End- of-Life Physician Education Resource Center. Retrieved April 23, 2001, from: http://www.eperc.mcw.edu.

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As one investigator noted, “All episodes of delirium . . . interfere with meaningful inter- In patients with delirium, discontinuing unnecessary drugs or personal contact with loved ones due to prolonging the dosing interval for necessary drugs may help 4 clouding of consciousness.” Because the to clear the sensorium. period before death can be a last chance for the patient and family members to mend relationships, share dreams and say good-bye, it is imperative that measures be instituted to the use of bladder catheterization, and iatro- control delirium. genic events such as frequent room or staff Common causes of delirium near death changes or a disruptive environment with include hypoxia, infections (e.g., simple uri- excess noise that may disrupt sleep.6,7 nary tract infection), fever, dehydration and Altered mental status may be precipitated opioid or benzodiazepine withdrawal. As the by a combination of therapies. Anesthetics, time of death approaches, hepatic and renal analgesics, antibiotics, anticholinergics, anti- function deteriorates, and patients become hypertensives, antiarrhythmics, anticonvul- more vulnerable to delirium, particularly sants, histamine H1 and H2 antagonists, and delirium caused by medications. Discontinu- other drugs have been associated with the ing unnecessary drugs or prolonging the dos- onset of delirium in patients treated in inten- ing interval for necessary drugs may help to sive care units (ICUs).7 According to one clear the sensorium. group of investigators,7 what has been called A recent study5 found that despite a high “ICU psychosis (or syndrome)” is actually a incidence (88 percent), delirium was re- true delirium caused by organic stressors; as versible in approximately 50 percent of dying such, it should be promptly noted and patients. In this study, opioids, other psy- aggressively managed, rather than tolerated choactive medications and dehydration were or ignored. the most frequent causes of reversible delir- The two goals of symptomatic care in the ium. Dehydration is usually asymptomatic in dying patient are to determine the cause of terminally ill patients; however, when dehy- the mental status symptoms and to institute dration results in delirium, gentle rehydration measures to control these symptoms as they may be beneficial if there is a need for the affect the quality of life for the patient and patient to be more alert. family. Hospice workers often observe “termi- Another study6 identified factors associated nal restlessness” as a sign that death is with an increased risk of delirium in patients approaching.8 If delirium occurs close to the older than 80 years. These risk factors included time of death, the patient’s agitation may sim- impaired vision (Snellen test score worse than ply be observed, with attention given to pre- 20/70), severe illness (Acute Physiology and venting physical harm. Alternatively, the Chronic Health Evaluation II score higher than patient may require sedation for the comfort 16), cognitive impairment (Mini-Mental State of all involved in care. Terminal sedation is a Examination score lower than 24) and dehy- treatment of last resort and is beyond the dration (blood urea nitrogen level higher than scope of this article. Full discussions of this 18 mg per dL [6.5 mmol per L]). subject are available in the literature.9-11 In addition to reducing risk factors for Hospice workers have noted that a changed delirium, the physician may be able to pre- mental status is more pronounced in patients vent its onset in an elderly patient by avoiding who have been undergoing a significant five precipitating conditions: the use of phys- psychosocial or spiritual struggle. They would ical restraints, malnutrition, the addition of argue that sedation is not appropriate in this more than three new medications in one day, setting. For families, however, the open, star-

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The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

ing eyes and agitated movement of a patient terminally ill patients. Medications commonly may not be emotionally tolerable, resulting in used to manage delirium are listed in Table 2.14 a request for something to “quiet” the patient. Nonpharmacologic interventions for delir- Haloperidol is the agent of choice for the ium can also be of benefit. For example, a management of delirium associated with family member or other person (e.g., a sitter) hyperactivity at the end of life. A well- might remain with the patient to keep the designed, double-blind study8 comparing patient calm and prevent physical harm. Use haloperidol (a high-potency neuroleptic), of physical restraints should be avoided unless chlorpromazine (a low-potency neuroleptic) absolutely necessary; if required, restraints and lorazepam (a benzodiazepine) in the should be used in conjunction with sedation. treatment of delirium in hospitalized patients Patients’ descriptions of “visits” by loved with AIDS found haloperidol to be the pre- ones who have died before them should not ferred drug. Greater improvement of mental be mistaken for delirium or confusion. status symptoms occurred within 24 hours Although labeled by some as hallucinations, after the initiation of haloperidol in a low these encounters usually appear to be com- dosage (2.8 mg per day)8,12 than with neuro- forting to dying patients and consequently leptics given in previous trials.13 No extra- may not require medical treatment. pyramidal side effects were noted. The benzodiazepine arm was terminated before the end Dyspnea of the trial8 because of paradoxic agitation or Dyspnea, which is a subjective experience of oversedation. Studies have not been com- difficult or distressed breathing, has been pleted in other patient populations; thus, it is described in patients with cancer (70 percent), not clear whether these findings are true for all AIDS (11 to 62 percent) and other terminal

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illnesses.15(pp295-308)-20 One study21 noted that family physicians find dyspnea to be the most Objective findings may not adequately reflect the distress distressing symptom in dying patients. experienced by patients with dyspnea. One quarter of Objective findings may not adequately patients have no obvious etiology for the symptom. reflect the distress experienced by patients with dyspnea. The original hospice studies20 conducted during the late 1980s found that 75 percent of patients with cancer and lung tomatic treatment of dyspnea. In some stud- involvement had dyspnea; however, of those ies,28,29 opiates have been reported to increase with dyspnea who were entered in hospice exercise tolerance and reduce the perception programs, only 39 percent had primary lung of breathlessness in patients with chronic problems. In the same studies, fully 24 per- obstructive pulmonary disease. Other stud- cent of patients with dyspnea had no obvious ies30-32 have not been able to substantiate this etiology for the symptom. Hence, not all benefit. More clinical trials are needed. patients with dyspnea have severe pulmonary A recent study33 at St. Christopher’s Hospice pathology or tachypnea, and vice versa. This in London found that titrated oral morphine distinction is important because symptomatic treatments are directed toward the end point of relieving the symptom (dyspnea), TABLE 3 not the sign (tachypnea). Recommended Treatments for Dyspnea The pathophysiology of dyspnea can reflect in End-of-Life Care Based on Etiology* the regulation of breathing (central, psychiatric), the act of breathing (weakened inter- Etiology Treatment costal muscles) or the need to alter breathing Anemia Transfusion, erythropoietin† patterns because of increased activity or Hypoxia Increase fraction of inspired oxygen. 22,23 hypoxia. Tools for measuring dyspnea Superior vena cava Radiation; corticosteroids in high dosage include the Medical Research Council compression 24 method, the Support Team Assessment Lymphangitic tumor Corticosteroids in high dosage (short term only) Schedule25 and the European Organization spread for Research and Treatment of Cancer Qual- Pleural effusion Thoracentesis, chest tube, pleurodesis ity of Life Questionnaire (EORTC QLQ-C30; Pericardial effusion Aspiration, pericardial window used in many cancer studies).26 In addition, a Cardiovascular disease Diuretic, possible irradiation visual analog or numeric scale can be Pulmonary embolus Anticoagulation, possible filter (antibiotics) employed at the bedside to record the degree Chronic obstructive Bronchodilators (aerosolized), corticosteroids, antibiotics of dyspnea experienced by the patient. pulmonary disease The treatment of dyspnea is best directed Infections Antibiotics, antifungals or antivirals; corticosteroids at the underlying cause (if known). Some Anxiety Benzodiazepines, environmental interventions causes and appropriate interventions are listed in Table 3.15(pp295-308) The most com- *—See also Table 4. mon reversible causes of dyspnea are bron- †—The physician can decide if it is reasonable to use erythropoietin in a termi- chospasm (52 percent), hypoxia (40 percent) nally ill patient. Although treatment can be beneficial in relieving fatigue and improving quality of life, it is expensive and must be given for 4 to 6 weeks 27 and anemia (20 percent). before benefits become apparent. Giving a dosage of 10,000 units daily for two When dyspnea is not reversible by specific weeks may reduce this time. cause-directed treatment, symptomatic treat- Adapted with permission from Berger A, Portenoy RK, Weissman DE, eds. Princi- ment is given (Table 4). Opiates, titrated to ples and practice of supportive oncology. Philadelphia: Lippincott-Raven, 1998: achieve the desired effect with acceptable tox- 295-308. icity, are considered the mainstay of the symp-

SEPTEMBER 15, 2001 / VOLUME 64, NUMBER 6 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1023 improved dyspnea in 60 percent of patients opioids administered by oral, subcutaneous with terminal cancer. However, significant and inhaled (nebulizer) routes, with the short-term adverse effects (particularly seda- dosage titrated to a level at which the symp- tion) occurred, causing some patients to drop tom is relieved. Benzodiazepines, titrated out of the trial. The authors of the study until dyspnea is relieved, are commonly advised physicians to inform patients with dys- added to the opioid regimen to alleviate the pnea about the side effects of opioids and to anxiety associated with breathlessness. monitor carefully for such effects. Nonpharmacologic measures can also be of Given these caveats, many physicians who great value. Interventions include providing provide palliative care manage dyspnea with good air movement near the patient, keeping cool room temperatures, and proposing and instituting measures to minimize the patient’s TABLE 4 exertion or anxiety. Movement of air by a fan Symptomatic Management of Dyspnea in End-of-Life Care may calm the patient. The administration of oxygen or air can significantly reduce dyspnea Nonpharmacologic therapy in patients with advanced cancer.34 Promote good air movement around the patient. Measures designed to minimize stress can Provide cool room temperature, as tolerated by the patient. be useful in treating dyspnea. Exertion on the Explain to the family that external signs (e.g., tachypnea) may not indicate part of the patient can be limited by provid- patient discomfort. ing a bedside commode, using a wheelchair Humidify the air that the patient breathes. Maintain the patient in a sitting position. for transport and avoiding exposure to hot, Minimize the patient’s distress by encouraging the family to avoid having humid weather or extreme temperatures. disagreements in front of the patient. Postural drainage techniques may be helpful. Minimize the patient’s exertion by providing a bedside commode and Family members should be taught to inquire transporting the patient by wheelchair; avoid exposure to hot, humid weather specifically about the patient’s comfort, in and extreme temperatures. that external signs may appear quite distress- Provide postural drainage. ing to the family but may not seem unusual to Have the nursing staff or family give the patient massages and provide distraction with music or by reading aloud to the patient. the patient. Family members and friends can Provide oxygen, or a fan in the patient’s room. lessen the patient’s distress by avoiding dis- Visit the patient. agreements in front of the patient. Consult the hospice team. Patients with dyspnea often prefer sitting Pharmacologic therapy with their body leaning forward and their Opioids* arms resting on a table. Prolonged use of this Mild dyspnea position may result in muscle aches and sore- Hydrocodone, 5 mg orally every 4 hours ness, which can be relieved with opioids. Acetaminophen-codeine (Phenaphen; 325 mg/30 mg), one capsule Some patients appreciate massage or other orally every 4 hours distractions, such as listening to music or to a Severe dyspnea book being read aloud. Morphine, 5 mg orally; titrate dose every 4 hours. A visit from the physician to offer care and Oxycodone (Roxicodone), 5 mg orally; titrate dose every 4 hours. reassurance is invaluable to the patient and Hydromorphone (Dilaudid), 0.5 to 2 mg orally; titrate dose every 4 hours. Benzodiazepines: titrate dosage to reduce anxiety component. family. An interdisciplinary approach, such as Bronchodilators that provided by hospice, can be very helpful. Corticosteroids Final Comment *—In opiate-naïve patients, use the listed starting dosage and titrate until symp- This two-part article has focused on some toms are relieved. of the most common symptoms patients may experience at the end of life. Dying patients

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may also suffer from other symptoms, includ- 7. McGuire BE, Basten CJ, Ryan CJ, Gallagher J. Inten- sive care unit syndrome: a dangerous misnomer. ing pressure sores, edema, ascites, bowel Arch Intern Med 2000;160:906-9. impaction, diarrhea, hemoptysis, pleural effu- 8. Breitbart W, Marotta R, Platt MM, Weisman H, sions, incontinence, urinary retention, hema- Derevenco M, Grau C, et al. A double-blind trial of turia and fever. The management of these dis- haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. orders is discussed in various palliative care Am J Psychiatry 1996;153:231-7. textbooks and training programs.15,35-39 9. Miller FG, Meier DE. Voluntary death: a comparison The End-of-Life Physicians Education of terminal dehydration and physician-assisted suicide. Ann Intern Med 1998;128:559-62. Resource is a superb Internet source for pallia- 10. Quill TE, Lo B, Brock DW. Palliative options of last tive care–related educational materials (http:// resort: a comparison of voluntarily stopping eating www.eperc.mcw.edu). For no charge, the and drinking, terminal sedation, physician-assisted suicide, and voluntary active euthanasia. JAMA entire Education for Physicians on End-of-Life 1997;278:2099-104. Care Participant’s Handbook can be down- 11. Quill TE, Byock IR. Responding to intractable termi- loaded from the Internet (http://www.epec. nal suffering: the role of terminal sedation and voluntary refusal of food and fluids. ACP-ASIM End- net/content/participantshandbook.html). of-Life Care Consensus Panel. American College of Note that health care providers should use Physicians–American Society of Internal Medicine. clinical judgment and consult official pre- Ann Intern Med 2000;132:408-14. 12. Lawlor PG, Fainsinger RL, Bruera ED. 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