Marc A. Sweeney and Phyllis A. Grauer
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the philosophy of palliative care and its impact on drug therapy.
2. Discuss the therapeutic management of palliative care patients and how it differs and is similar to traditional patient care.
3. List the most common symptoms experienced by the terminally ill patient.
4. Explain the pathophysiology of the common symptoms experienced in the terminally ill patient.
5. Assess the etiology of symptoms in the terminally ill patient.
6. Describe the pharmacologic rationale of drug therapy used for symptom management in the terminally ill patient.
7. Recommend nonpharmacologic and pharmacologic management for symptoms in a terminally ill patient.
8. Develop a patient monitoring plan for palliative care management.
9. Educate patients and caregivers regarding palliative care management plan, including rationale of treatment, assessment of success and importance of adherence.
KEY CONCEPTS
According to the World Health Organization (WHO), “Palliative care is defined as the active total care of patients whose disease is not responsive to curative treatment. The goal of palliative care is to achieve the best quality of life for patients and their families.”
The goals of palliative care include enhancing quality of life while maintaining or improving functionality.
Palliative care is appropriate for all incurable diseases including cancer; chronic obstructive pulmonary disease; dementia, including Alzheimer’s disease; Parkinson’s disease; chronic cardiac disease; stroke, renal failure; hepatic failure; multiorgan failure; diabetes mellitus; etc.
Following a complete assessment of the patient, developing a comprehensive therapeutic plan that utilizes the fewest number of medications to achieve the highest quality of life is essential.
Palliative care is more than just pain management. It includes the treatment of symptoms resulting in the discomfort for the patient, which may include nausea, agitation, anxiety, depression, dyspnea, cachexia, constipation, diarrhea, pressure ulcers, edema, etc.
Involving the patient and caregivers into the development of the therapeutic plan demonstrates responsible palliative medicine.
Assessing positive therapeutic outcomes includes resolution of symptoms while minimizing adverse drug events.
Patient and caregiver education is vital to ensuring positive outcomes.
INTRODUCTION
According to the World Health Organization (WHO), “Palliative care is defined as the active total care of patients whose disease is not responsive to curative treatment. The goal of palliative care is to achieve the best quality of life for patients and their families.”1 Since the word, “palliate,” literally means “to cloak,” the WHO goal of achieving high quality of life is consistent with managing disease-related symptoms.2 Palliative care is an approach to care focusing on patients and their families and the challenges they face associated with life-threatening illness.3 The goal of care is to prevent and relieve suffering by means of early identification, assessment and treatment of pain and other physical symptoms, including associated psychosocial, emotional, and spiritual concerns.1 The WHO goes on to state that the most effective palliative care is provided by a team of health care professionals. Palliative medicine is rapidly becoming a well-recognized medical specialty throughout the world4. This expanding specialty in medicine is much needed due to the increased number of patients with chronic, slowly debilitating diseases.2
The term palliative care is frequently used synonymously with hospice, and although hospice programs provide palliative care, palliative care has a much broader application. The goals for both types of care are similar; however, differences exist. In the United States, hospice is defined by Medicare and other third-party payers as a medical benefit available to individuals who have 6 months or less life expectancy if the disease runs its typical course.5Hospice care guidelines and regulations are typically defined by federal regulations. Palliative care, on the other hand, may be provided at any point during the disease process and is not limited to the last 6 months of life as is the case with hospice care. Patients and families may receive some aspects of palliative care beginning at the time of diagnosis of a life-limiting illness. Palliative care, whether it is through a hospice program or a palliative care service may be delivered to patients in all care settings including the hospital, outpatient clinic, extended care facility, or at home.6
Palliative care is not only a philosophy of patient care, but also a highly organized system to deliver care.7 The foundation for providing quality palliative care centers around the active participation of an interdisciplinary group or team of professionals who work closely together to meet the goals of the patient and family. Palliative care team members include representatives from medicine, nursing, social work, pharmacy, chaplaincy, nutrition, rehabilitation, and other professional disciplines. The involvement of multiple disciplines provides a holistic approach to the patient’s care. Figure 4–1 provides a diagrammatic view of how a palliative care team may work together in caring for the patient.
The goals of palliative care include enhancing quality of life while maintaining or improving functionality.8 Given this goal of patient care, palliative care should most logically be delivered to patients from the onset of any chronic, life-altering disease. Palliative care is not a new concept, in fact, it is one of the oldest approaches to patient care. Before many of our modern medical and therapeutic advancements were developed, curative treatments were not normally available9. Provision of comfort and addressing quality of life during illness was considered the mainstay for patient care. During the 20th century, advances in medical care, nutrition, public health, and trauma care resulted in fewer patient deaths attributed to acute illness or injury. Medical management shifted focus from comfort to a death-denying approach with prolonging life as the primary goal. With this shift in focus, palliative care became less of an emphasis until 1967, when the first modern hospice was established in London, England. Today the palliative care philosophy attempts to combine enhanced quality of life, compassionate care, and patient and family support with modern medical advances.
FIGURE 4–1. An illustrative view of how a palliative care team works together.
EPIDEMIOLOGY AND ETIOLOGY
Although the modern hospice model of care originated in England in 1967, the first hospice in the United States was founded in 1974. Since that time, hospice acceptance and utilization has increased in the United States. The number of Medicare beneficiaries enrolled in hospice increased by 100% between 2000 and 2005.10 Medicare spending for hospice care tripled during that same time period, reflecting a greater number of patients receiving the benefits of this type of care. The Medicare Hospice Benefit is now the fastest growing benefit in the Medicare program, representing 3% of Medicare costs.11 The growth between the early 1990s and 2005 was significant.
When the hospice Medicare benefit was introduced in 1982, most patients had a terminal diagnosis of cancer, representing over 90% of beneficiaries.12 In 2005, less than 50% of patients receiving the Medicare Hospice Benefit have a cancer diagnosis, with the majority of hospice patients having other chronic or life-limiting diseases. Unfortunately, the average length of time a patient receives hospice care also decreased over time. Initially, the mean length of stay was 70 days per patient, but in 2005, the mean length of stay fell to approximately 20 days, resulting in less time for patients and families to benefit from the many services offered through hospice care.
Because palliative care and hospice have not typically been part of the traditional medical mindset, ongoing education has been directed toward physicians and other health care professionals to encourage them to introduce palliative care before a life-limiting disease has progressed to advanced stages. The goal is to offer hospice to patients when they have several months of life expectancy rather than waiting until the last days or weeks of life. In order to accomplish that, physicians are encouraged to discuss advanced care planning with individuals at the time of diagnosis of any chronic, life-limiting disease. As the health care community and the public recognize that psychosocial, spiritual, and emotional support of the patient, family, and caregiving system provides the foundation for coping with changes as patients decline, health care professionals are beginning to incorporate aspects of palliative care in the treatment plan sooner.
As health care providers recognize the benefit of palliative care for patients with any life-limiting illness, the approach to patient care has expanded beyond the cancer model of care. Understanding differences and similarities in pathophysiology of various disease states and their respective symptoms equips palliative care providers to develop appropriate individualized plans of care for their patients.
PATHOPHYSIOLOGY
In many respects, understanding the pathophysiology of multiple end-stage disease states is daunting, yet, in palliative care, the emphasis is not so much on the disease as it is on the associated physical, psychological, social, and spiritual symptoms. Palliative care focuses on symptom management for patients with progressive, life-limiting illnesses from diagnosis through death where the pathophysiological impact of disease on a patient’s symptoms may vary greatly depending on the stage of a patient’s illness. Palliative care is appropriate for all incurable diseases including cancer; chronic obstructive pulmonary disease; dementia, including Alzheimer’s disease; Parkinson’s disease; chronic cardiac disease; stroke; renal failure; hepatic failure; multiorgan failure; diabetes mellitus; etc.
For the purpose of this chapter, pathophysiology will not be a primary focus. Rather, the philosophy of managing physical, psychological, social, and spiritual symptoms in order to maintain quality of life and prevent suffering is discussed within the context of progressively incurable illnesses. This philosophy frequently deviates from principles and concerns related to the management of patients where prolonging life is the goal.
CLINICAL PRESENTATION AND DIAGNOSIS
Cancer
Palliative care is most commonly associated with patients who have cancer. Regardless of whether or not the cancer is curable, most patients have various degrees of physical, psychological, social, and spiritual symptoms which arise once a diagnosis is confirmed. The primary site of solid tumor and hematologic cancers associated with limited life include, but are not limited to, lung, bronchus, breast, colon, rectum, pancreas, prostate, ovaries, uterus, brain, esophagus, liver, kidneys, bladder, lymph system, bone marrow, and skin. The spread of cancer cells (metastases) to distant areas are associated with poorer prognosis. Once a cancer patient has failed curative and life-prolonging therapy, prognosis and disease trajectory is easier to determine than in patients with other life-limiting diseases. The change in focus from cure to symptom control becomes apparent and, therefore, more acceptable. Symptoms associated with cancer are dependent on both the primary tumor site and the location of metastatic spread. Symptoms may also result from the effects of cancer treatments such as chemotherapy and radiation. (See Chaps. 88–99 for specific cancers and their treatments.)
End-Stage Heart Failure
Heart disease is the leading cause of death by disease. Many forms of heart disease result in sudden death; however, the disease progression of heart failure is protracted yet unpredictable. Advanced heart failure (class III–IV or stage C or D) is characterized by persistent symptoms that limit activities of daily living despite optimal drug therapy. Common symptoms include fatigue, breathlessness, anxiety, fluid retention, and pain. In heart failure, standard medication management is intended to reduce the progression of cardiac remodeling and is considered disease modifying (Fig. 4–2). However, with the exception of cholesterol-lowering agents, these same cardiac medications are also palliative and should not be discontinued prematurely without cause. Exacerbations of heart failure symptoms should be aggressively treated as long as the patient is responsive to therapy and wishes to receive treatment. In hospice, this can often be accomplished through medication manipulation in the patient’s home without the need for hospitalization (see Chap. 6).
Patient Encounter 1
TS is a 78-year-old white female admitted to a hospice program for palliative care. The patient has a primary diagnosis of breast cancer with metastases to the lung and bone. TS has a past medical history that includes chronic heart failure (CHF), hypothyroidism, osteoporosis, and gastroesophageal reflux disease (GERD). She has no known drug allergies. The patient’s chief complaint upon admission is pain that is rated 5 on the pain scale (0–10), nausea and vomiting, depression, and constipation. She describes her pain as an aching pain in the areas of her bone metastases. The pain increases with movement. She also has a constant deep pain in her left chest area but it is not as severe. TS is currently bedbound.
VS: BP 120/82, RR 40, P 100, wt 44.5 kg (98 lb), ht 5’4”
Meds: Albuterol two inhalations every 2 hours; digoxin 0.25 mg by mouth daily; omeprazole 40 mg by mouth daily; furosemide 40 mg by mouth twice daily; oxycodone/acetaminophen 10/325; 1–2 tablets by mouth every 4 hours as needed; fentanyl patch 50 mcg/h; apply one patch every 72 hours; levothyroxine 25 mcg by mouth daily; alendronate 70 mg by mouth weekly; celecoxib 100 mg by mouth daily; multivitamin 1 tablet by mouth daily
What are potential etiologies of the nausea and vomiting TS is experiencing?
What type of the pain is TS experiencing?
What questions would you ask TS during your assessment?
What potential drug–drug interactions may exist and how would you monitor the patient for them?
Outline three interventions that the practitioner should make to improve the care of TS.
FIGURE 4–2. Drugs, their use in Class III–IV heart failure, and their effects on survival, hospital admissions, and functional status. →, survival does not increase or decrease, but stays the same; ↑, survival increases. (Data from Ref. 8, p. 172.)
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) has a prolonged and variable course. Patients with COPD have a high number of physician visits and hospital admissions. Palliative care treatment is directed at reducing symptoms, reducing the rate of decline in lung function, preventing and treating exacerbations, and maintaining quality of life. In end-stage COPD, bronchodilators and anti-inflammatory agents become less effective. Symptoms of late-stage disease include wheezing, chronic sputum production, cough, frequent respiratory infections, dyspnea with exertion progressing to dyspnea at rest, fatigue, pain, hypoxia, and weight loss. Pulmonary hypertension frequently occurs and can lead to cor pulmonale or right-sided heart failure (see Chap. 15).
End-Stage Renal Disease
Chronic kidney disease is progressive and leads to renal failure. In end-stage renal disease (ESRD) the only life-sustaining treatments are dialysis or renal transplant. Without treatment, kidney failure causes uremia, oliguria, hyperkalemia and other electrolyte disorders, fluid overload and hypertension unresponsive to treatment, anemia, hepatorenal syndrome, and uremic pericarditis. Symptoms associated with chronic kidney disease (stage 5) include fatigue, pruritus, nausea, vomiting, constipation, dysgeusia, muscle pain, and bleeding abnormalities. Palliative care in these patients includes the minimization of listed symptoms; however, because many options for drug therapy will be cleared through the kidneys, agents should be chosen cautiously to avoid other complications (see Chap. 26).
End-Stage Liver Disease
Like kidney disease, the only treatment to prolong life in advanced liver disease is transplant. Patients with end-stage liver disease typically present with ascites, jaundice, pruritus, or encephalopathy and frequently with all four symptoms. Additionally, bleeding disorders are common and associated esophageal or gastric varices bleeds are the cause of death in about one-third of those who die from liver disease. Palliative care in these patients focuses on the symptom management of end-stage liver disease complications.
HIV/AIDS
Pharmacologic advances have changed the prognosis and progression of HIV/AIDS. Today, palliative care is predominately directed toward patients who have not had access to drug therapy in the early stages of their disease. Patients with progressed HIV/AIDS are susceptible to acquire opportunistic infections and cancer which may hasten their death. Common symptoms observed in individuals with HIV/AIDS at the end of their life include fatigue, profound weight loss, breathlessness, nausea, GI disturbances, and pain. The goal of palliative care in these patients is to minimize common AIDS-related symptoms (see Chap. 87).
Stroke/Cerebral Vascular Accident
Stroke can be a result of hemorrhage or ischemia. The prognosis of patients who have had a cerebral vascular accident (CVA) is unpredictable and may be extended, resulting in caregiver fatigue. Approximately one-third of patients who have a stroke will die within 2 years. Patients with stroke deal with loss of physical and cognitive function, poststroke pain and frequent depression. Incontinence, aphasia and dysphagia and seizures are also common. Patients who have dysphagia have a high incidence of aspiration pneumonia, which often is the cause of death (see Chap. 11).
Parkinson’s Disease
Parkinson’s disease is a degenerative neurologic disease with a long chronic, progressive course evidenced by akinesia, rigidity, and tremor. The goal of therapy is to reduce symptoms and maintain or improve quality of life. Palliative care provides support to both the patient and caregiving system as patients become more disabled and as neuropsychiatric problems arise. Symptoms that frequently occur are skin infections and breakdown, constipation, pain, depression, hallucinations, and confusion. Individuals with Parkinson’s disease often die from bronchial pneumonia due to dysphagia and complication from falls (see Chap. 32).
Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder that is characterized by progressive loss of motor neurons. The median survival is approximately 3 years from the onset of symptoms with less than 15% of patients surviving 10 years. Initially symptoms of ALS present as limb weakness, with other symptoms developing in no particular order including cramps, spasticity, pain, dysarthria, sialorrhea, fatigue, insomnia, depression, fear and anxiety, involuntary emotional expression disorder, constipation, aspiration, and laryngospasm. Many patients do not have cognitive impairment; however, one-fourth to one-half of patients with ALS may have associated frontal lobe dementia. Disease progression eventually involves all systems except sphincter control and eye movement. Unless the individual has long-term mechanical ventilation, the cause of death is typically respiratory failure.
Alzheimer’s and Other Dementia
Dementia is a progressive, nonreversible deterioration in cognitive function with associated behavioral dysfunction. Alzheimer’s disease accounts for the majority of dementia cases while vascular, Parkinson’s disease, dementia with Lewy body, and frontotemporal dementias are less prevalent. Drug therapy is targeted at slowing the progression of the cognitive symptoms and preserving the patient function. As patients progress toward end-stage dementia, in addition to memory loss and personality and behavioral changes, they require assistance in basic activities of daily living such as feeding, dressing, and toileting. At this point they may not respond to their surroundings, may not communicate, or have impaired movements and dysphagia. Depression, agitation, delusions, compulsions, confusion, hallucinations, incontinence, and disruption of sleep/wake cycles are all common symptoms in end-stage dementias. Assessment of symptoms is challenging due to the cognitive impairment and frequent aphasia. Palliative care is not only directed toward the patient but also emotional support is needed for those close to them (see Chap. 35).
TREATMENT
Following a complete assessment of the patient, developing a comprehensive therapeutic plan that utilizes the fewest number of medications to achieve the highest quality of life is essential. Many times, one drug may provide relief for multiple symptoms, resulting in better patient care, lower costs, and fewer medications for the patient to take. Cost-effective drug recommendations are essential for hospice agencies to control costs, given that Medicare and most other third-party payors reimburse hospice at a fixed per-diem rate. Avoiding polypharmacy will reduce the incidence of adverse drug events related to drug interactions, excessive side effects, and duplications of therapy. The following list of symptoms addressed by palliative care includes common symptoms observed in end of life; however, it is not comprehensive. Palliative care is more than just pain management. It includes the treatment of symptoms resulting in the discomfort for the patient, which may include nausea, agitation, anxiety, depression, dyspnea, cachexia, constipation, diarrhea, pressure ulcers, edema, etc.
It should be noted that many drugs used for the treatment of symptoms in end-of-life care are often prescribed for unapproved uses, administered by unapproved routes or in dosages higher than that recommended by the package insert. This “off-label” use of medication is not unique to palliative care.
Anxiety
A comprehensive review of anxiety disorders may be found in Chapter 40.
Palliative Care Considerations
• Anxiety is “a state of fearfulness, apprehension, worry, emotional discomfort, or uneasiness that results from an unknown internal stimulus, is excessive, or is otherwise inappropriate to a given situation.”13
• Anxiety is closely related to fear, but fear has an identified cause or source of worry (e.g., fear of death). Fear may be more responsive to counseling than an anxiety state that the patient cannot attribute to a particular fearful stimulus. Anxiety disorders are the most prevalent class of mental disorders overall, so it is not surprising that anxiety is a common cause of distress at life’s end.14
• In addition to anxiety disorders, a variety of conditions can cause, mimic, or exacerbate anxiety15,16:
• Delirium, particularly in its early stages, can easily be confused with anxiety.
• Physical complications of illness, especially dyspnea and undertreated pain, are common precipitants.
• Significant anxiety is present in the majority of patients with advanced lung disease and is closely related to periods of oxygen desaturation.
• Medication side effects, especially akathisia from older antipsychotics and antiemetics (including and especially metoclopramide), can present as anxiety.
• Interpersonal, spiritual, or existential concerns can mimic anxiety.
• Patients with an anxious or dependent coping style are at high risk of anxiety as a complication of advanced illness.
• Short of making a diagnosis of a formal anxiety disorder, differentiating normal worry and apprehension from pathologic anxiety requires clinical judgment.
• Behaviors indicative of pathological anxiety include:
• Intense worry or dread
• Physical distress (e.g., tension, jitteriness, or restlessness)
• Maladaptive behaviors (e.g., treatment nonadherence, social withdrawal, or avoidance)
• Diminished coping and inability to relax
• Pathologic anxiety may be complicated by insomnia, depression, fatigue, GI upset, dyspnea, or dysphagia. Anxiety can also worsen these conditions if they are already present.
• Untreated anxiety may lead to numerous complications, including withdrawal from social support, poor coping, limited participation in palliative care treatment goals, and family distress.
• Reassess the patient for anxiety with any change in behavior or any change in the underlying medical condition.
• Search for probable etiologies
• Assess for formal anxiety disorders
• Assess for other contributing factors
• Appropriate assessment of anxiety is key to its management.
Nonpharmacologic Treatment in Palliative Care
Regardless of what treatment approach is chosen, the following principles apply:
• Offer emotional support and reassurance when appropriate.
• Err on the side of treatment—be willing to palliate anxiety.
• Assess treatment response and side effects frequently.
• Aim to provide maximum resolution of anxiety.
• Educate patients and families about anxiety and its treatments.
• Psychotherapies can help in the management of anxiety, though the availability of trained therapists willing to make home visits, and limited stamina and attention span of seriously ill patients, typically make such therapies impractical in the hospice setting.
• Cognitive and behavioral therapies can be beneficial, including simple relaxation exercises or distraction strategies (i.e., focusing on something pleasurable or at least emotionally neutral).
• Encourage chaplain visits, especially if spiritual and existential concerns predominate.
• When an underlying cause of anxiety can be identified, treatment is initially aimed at the precipitating problem, with monitoring to see if anxiety improves or resolves as the underlying cause is addressed.
Pharmacotherapy in Palliative Care
• In most cases, management of pathological anxiety in the hospice setting involves pharmacologic therapies. Benzodiazepines are the gold standard for treatment; however, selective serotonin reuptake inhibitors (SSRIs), typical and atypical antipsychotics, and tricyclic antidepressants may also be appropriate.17
• The primary goal of therapy for anxiety in hospice is patient comfort. Aim to prevent anxiety, not just treat it with as needed medications when it flares. Think of pain management as an analogy.
• Start at the lower end of the dose range of a given anxiolytic agent to prevent unnecessary sedation, but recognize that standard or higher doses may be required.
• Avoid use of bupropion and psychostimulants for anxiety. While effective for depression, they are ineffective for anxiety and may make anxiety worse.
• Lorazepam, alprazolam, and diazepam are commonly crushed and placed under the tongue with a few drops of water for patients who have difficulty swallowing.
• Low dose haloperidol is also used to treat anxiety in palliative care particularly if delirium is present.
• Chapter 40 provides more detailed information on appropriate use of anxiolytic agents.
Delirium
Palliative Care Considerations
• Delirium is a very common disorder in hospice, occurring in more than 80% of terminally ill patients, most often in the last few days of life.13
• Potential causes of delirium in the hospice setting include, but are not limited to, medical illness, dehydration, hypoxia, metabolic disturbances, sepsis, side effects of drugs, urinary retention, constipation or impaction, uncontrolled pain, or alcohol or drug withdrawal.18,19
• A classic symptom of delirium is clouding of consciousness. This can be manifested by an inability to either maintain or shift attention. Patients also have impaired cognitive functioning, which may or may not include memory disturbances.
“Sundowning” is very common phenomenon in end of life and especially in the presence of delirium. It presents as daytime sleepiness and nighttime agitation and restlessness.
• Another common characteristic is fluctuation in severity of delirium symptoms during the course of the day. This can even occur within the course of a single hour or also from day to day.
• Patients who exhibit agitation from their delirium are easy to identify, but those who present as withdrawn and with diminished responsiveness (“quiet” delirium) are more difficult to diagnose. It is not uncommon for patients to exhibit both quiet and agitated delirium. Treatment is the same for both types of delirium.
• Delirium is difficult to distinguish from dementia. Delirium more commonly presents as a sudden onset (e.g., hours to days), with an altered level of consciousness and a clouded sensorium. However, dementia more commonly presents gradually and with an unimpaired level of consciousness.
Nonpharmacologic Treatment in Palliative Care
• Establishing a safe, soothing environment where there are familiar objects such as photographs and familiar music can be helpful to calm the patient.
• Minimizing risk of injury is important when the patient is agitated.
• Providing education to families and caregivers about the causes of delirium, signs and symptoms, and how to best manage it will help to reduce their anxiety and distress when it occurs.
Pharmacotherapy in Palliative Care
• The most important initial step is to determine the goal of care. If possible, reverse the underlying cause of delirium in order to restore the patient to a meaningful cognitive status.18
• If the precipitating factors cannot be reversed, initiate therapy to treat the symptoms. Patients who are not agitated may not require any treatment other than comfort measures. If the patient is irreversibly delirious and agitated, drug therapy is generally indicated.
• Neuroleptic drugs (conventional or atypical antipsychotics) are the drugs most commonly used to treat confusion and agitation associated with delirium. However, treatment of delirium with these drugs is an “off-label” indication.
• Atypical antipsychotics such as risperidone, olanzapine, quetiapine, ziprasidone, paliperidone, and aripiprazole account for a major portion of increasing medication costs in the geriatric population.20
• Haloperidol, when given in doses less than 2 mg/day is well-tolerated and nonsedating and is within the recommended dosing parameters for long-term care facilities.
• When sedation is beneficial for terminal aggressive, agitated delirium, chlorpromazine is useful to provide patient comfort as they approach death. When patients are bedbound and in the final stages of life, orthostatic hypotension common with chlorpromazine is not a concern.
• Haloperidol and chlorpromazine are commonly given sublingually or rectally if swallowing becomes difficult, although these are not approved routes of administration. Haloperidol, but not chlorpromazine, can be given subcutaneously.21,22
• Administering benzodiazepines alone in a patient with delirium can actually make the delirium and confusion worse, although it is sometimes helpful to add benzodiazepines along with antipsychotics if sedation is desired. Phenobarbital may also be used for this purpose
Dyspnea
Palliative Care Considerations
• Dyspnea is described as an uncomfortable awareness of breathing. It is a subjective sensation, and patient self-report is the only reliable indicator. Respiratory rate or Po2 often does not correlate with the feeling of breathlessness.23,24
• Respiratory effort and dyspnea are not the same. Patients may report substantial relief of dyspnea from opioids with no change in respiratory rate.
• The prevalence of dyspnea varies from 12% to 74% and tends to worsen in the last week of life in terminally ill cancer patients to between 50% and 70%.
Patient Encounter 2
JK is an 80-year-old white male admitted to hospice with a primary diagnosis of CHF. Other comorbidities include renal failure, diabetes mellitus, coronary artery disease, hyperlipidemia, anemia, arthritis and hypothyroidism. The patient also has a percutaneous endoscopic gastrostomy (PEG) tube, peripherally inserted central catheter (PICC) and Foley catheter. The patient has no known drug allergies. JK’s chief complaint is lower leg edema and shortness of breath.
Meds: Sliding scale insulin (e.g., regular insulin administered with fasting blood glucose greater than 250 mg/dL); potassium chloride 20 mEq daily via PEG; furosemide 20 mg twice daily via PEG; levothyroxine 88 mcg crushed daily via PEG; loperamide liquid 4 mg twice daily via PEG; famotidine liquid 20 mg daily via PEG; simvastatin 20 mg daily via PEG; ibuprofen liquid 400 mg every 6 hours via PEG
What potential interventions could the practitioner make to improve JK’s care?
What medications could be discontinued?
How does the presence of a percutaneous endoscopic gastrostomy tube impact the drug therapy decisions?
Would the use of a positive inotropic agent in this patient provide benefit? What would be the risks and benefits?
What potential drug–drug interactions may exist? How would you monitor the patient for them?
• A thorough history and physical examination should be taken and possible reversible causes of dyspnea should be identified and treated, if present.
Nonpharmacologic Treatment in Palliative Care
• Provide information and anticipate and proactively prepare the patient and family for worsening symptoms.
• Identify triggers that cause dyspnea attacks and minimize as much as possible.
• Educate patient and family regarding treatment of dyspnea, including the use of opioids.
• Prevent isolation and address spiritual issues that can worsen symptom.
• Encourage relaxation and minimize the need for exertion.
• Reposition to comfort, usually to a more upright position or with the compromised lung down.
• Avoid strong odors, perfumes, and smoking in the patient’s presence or in close proximity.
• Improve air circulation/quality.
• Provide a draft, use fans, or open windows.
• Adjust temperature/humidity with air conditioner or humidifier.
Pharmacotherapy in Palliative Care
• If no treatable causes can be identified or when treatments do not completely alleviate distressing symptoms, opioids are first-line agents for treating dyspnea.25,26
• Opioids suppress respiratory awareness, decrease response to hypoxia and hypercapnia, vasodilate, and have sedative properties.
• Low-dose opioids (e.g., starting oral dose of morphine approximately 5 mg) have been shown to be safe and effective in the treatment of dyspnea. Doses should be titrated judiciously.
• As anxiety can exacerbate dyspnea, benzodiazepines and antidepressants that have anxiolytic properties can be beneficial.27
• Once an effective dose of an opioid has been established, converting to an extended-release preparation may simplify dosing.
• When using opioids, anticipate side effects and prevent constipation by initiating a stimulant laxative/stool softener combination.
• Nebulized opioids for treatment of dyspnea are controversial. Study results have been inconsistent.28–30
• Nonrandomized studies, case reports, and chart reviews describe anecdotal improvement in dyspnea using nebulized opioids; however, several controlled studies using nebulized opioids have provided inconclusive or negative results.
• Nebulized opioids may be advantageous in patients that are not able to or willing to take an oral agent or cannot tolerate adverse effects of systemic administration.
• Fentanyl appears to be the safest nebulized opioid.
• Nebulized furosemide appears effective for dyspnea refractive to other conventional therapies.31–33
• Hypothesized mechanism of action of nebulized furosemide is its ability to enhance pulmonary stretch receptor activity, inhibition of chloride movement through the membrane of the epithelial cell, and its ability to increase the synthesis of bronchodilating prostaglandins.
• Oxygen therapy may be useful to patients with dyspnea and can reverse hypoxemia.
• For known etiologies of dyspnea, consider the following:23,25,27
• Bronchospasm or COPD exacerbation: Albuterol, ipratropium, and/or oral steroids should be used for symptoms management. Nebulizing bronchodilators are more effective than using handheld inhalers in patients who are weak and have difficulty controlling their breathing.
• Thick secretions: If cough reflex is strong, loosen secretions with guaifenesin or nebulized saline. If the cough is weak, hyoscyamine, glycopyrrolate, or scopolamine patch can effectively dry secretions.
• Anxiety associated with dyspnea: Consider benzodiazepines (e.g., diazepam, lorazepam).
• Effusions: Thoracentesis will be necessary.
• Low hemoglobin: Red blood cell transfusion (controversial) or erythropoietin (rarely used in hospice, but might have a larger role in palliative care patients).
• Infections: Antibiotic therapy as appropriate.
• Pulmonary emboli: Anticoagulants for prevention and treatment or vena cava filter placement (rarely used in hospice, but might have a larger role in palliative care patients).
• Rales due to volume overload: Reduction of fluid intake or diuretic therapy as appropriate.
Nausea and Vomiting
A comprehensive review of nausea and vomiting may be found in Chapter 20.
Palliative Care Considerations
• Up to 71% of palliative care patients will develop nausea and vomiting with approximately 40% experiencing these symptoms in the last 6 weeks of life. Chronic nausea can be defined as lasting longer than a week and without a well-identified or self-limiting cause, such as chemotherapy, radiation, or infection.34–37
• Four major mechanisms are correlated with the stimulation of the vomiting center (Fig. 4–3). Potentially reversible causes of nausea and vomiting should not be overlooked.
• Causes of chronic nausea in end-of-life patients may include: autonomic dysfunction, constipation, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), other drugs, infection, bowel obstruction, metabolic abnormalities (e.g., renal or hepatic failure, hypercalcemia), increased intracranial pressure, anxiety, radiation therapy, chemotherapy, or untreated pain.
Nonpharmacologic Treatment in Palliative Care
• Relaxation techniques may prove beneficial in some patients.
• Strong foods or odors should be avoided.
• If possible, eliminate offending medications.
Pharmacotherapy in Palliative Care
• The clinical features of nausea and vomiting should guide the choice of antiemetics used (for a more comprehensive review, refer to Chap. 20). The following are examples of managing nausea and vomiting as it correlates with the etiology:
• Chemoreceptor trigger zone (CTZ)-induced nausea and vomiting are caused by chemotherapeutic agents, bacterial toxins, metabolic products (e.g., uremia), and opioids. Dopamine (D2), serotonin (5-HT), and neurokinin-1 are the primary neurotransmitters involved in this process. Therapy is based on blocking D2 with D2-antagonists including butyrophenones (e.g., haloperidol), phenothiazines, and metoclopramide. Serotonin (5-HT3) antagonists (e.g., ondansetron) are mainly used for chemotherapy and radiotherapy-induced nausea.38,39
• Cerebral cortex-induced nausea and vomiting can be caused by anxiety, taste, and smell, as well as by increased intracranial pressure. Corticosteroids are administered to decrease intracranial pressure while anxiolytics such as benzodiazepines are used to treat the “anticipatory,” gustatory, and olfactory stimulation.
FIGURE 4–3. Mechanisms and associated neurotransmitters involved in nausea and vomiting.
• Vestibular nausea and vomiting is triggered by motion. Opioids can sensitize the vestibular center resulting in movement-induced nausea. Ambulatory patients are more susceptible to vestibular nausea and vomiting then bedbound patients. Because histamine and acetylcholine are the predominant neurotransmitters here, antihistamines and anticholinergics are the drugs of choice in movement-induced nausea and vomiting.
• GI tract stimulation occurs through vagal and sympathetic pathways. These pathways can be triggered by stimulation of either mechanoreceptors or chemoreceptors located in the gut. Gastric stasis, GI obstruction, drugs, metastatic disease, bacterial toxins, chemotherapeutic agents, and irradiation can lead to nausea and vomiting. Glossopharyngeal or vagus nerve stimulation in the pharynx by sputum, mucosal lesions, or infection (e.g., Candida) can also evoke nausea. The major neurotransmitters in the upper GI tract are D2, acetylcholine, and 5-HT. Metoclopramide blocks 5-HT4 and increases gastric motility above the jejunum, whereas anticholinergics will decrease GI spasticity and motility in nausea induced by gut hyperactivity. In high doses, metoclopramide will also act as a 5-HT3 antagonist.
• Autonomic failure causes gastroparesis resulting in anorexia, nausea, early satiety, and constipation. Delayed gastric emptying is frequently observed in patients with diabetes mellitus, chronic renal failure, and neurologic disorders. Malnutrition, cachexia, lung and pancreatic cancers, HIV, radiotherapy, and drugs such as opioids, anticholinergics, antidepressants, and vasodilators have been associated with autonomic failure and resulting chronic nausea, poor performance, tachycardia, and malnutrition.
• In addition to their usefulness in reducing intracranial pressure, corticosteriods have been found to be effective in nonspecific nausea and vomiting. The mechanism of this action is unknown.
• If nausea is due to gastritis, hiatal hernia, gastroesophageal reflux disease (GERD), or peptic ulcer disease, histamine2 (H2) antagonists or proton pump inhibitors (PPIs) should be administered.
• Refractory cases of nausea and vomiting often require judiciously selected combinations of medications from different classes (e.g., various combinations of haloperidol, metoclopramide, diphenhydramine, lorazepam, dexamethasone).
• Serotonin 3 (5-HT3) antagonists, such as ondansetron, granisetron, dolasetron, and palonosetron, have limited usefulness in nausea and vomiting due to terminal illness caused by their high specificity for serotonin3. They are typically indicated with emetogenic chemotherapy and up to 10 to 14 days post-treatment.
• Aprepitant is a neurokinin-1 antagonist that is indicated for the treatment of nausea due to highly emetogenic chemotherapy and in combination with a 5-HT3 antagonist and corticosteroid. Aprepitrant should not be used as a sole agent.
Pain
A comprehensive review of pain management may be found in Chapter 33.
Palliative Care Considerations
• According to the SUPPORT study, 74% to 95% of very ill or dying patients still experience uncontrolled pain.3 Although existing drug therapy affords the opportunity to manage over 90% of pain, many patients needlessly suffer.40
• As with any pain management, patient assessment is key to choosing appropriate therapeutic interventions. Because pain is subjective, both physical and humanistic factors must be considered.
• Patients in an end-of-life setting must also be evaluated for anxiety, depression, delirium, and other neurologic influences that may heighten a patient’s awareness or response to pain.
Nonpharmacologic Treatment in Palliative Care
• Nonpharmacologic treatment is essential in chronic pain management.
• Physical, complementary, and cognitive behavioral interventions reduce the perception of pain and decrease the dose requirements of medications. Examples of such strategies may include education and information about medical treatments (e.g., misconceptions about pain medications), massage, ice, heat, physical therapy, music therapy, imagery, pet therapy, psychotherapy, etc.
Pharmacotherapy in Palliative Care
• The WHO’s approach to pain management is still appropriate for most nociceptive pain (see Chap. 33).
• Pain should be assessed thoroughly and frequently, especially at the onset of treatment.
• For chronic, constant pain, around the clock dosing of analgesics are usually necessary.41,42
• When titrating opioid doses, increase daily maintenance doses by 25% to 50% if patients are requiring two to three breakthrough doses per 24 hours. The dose of opioids for the treatment of breakthrough pain should be equal to 5% to 15% of the daily maintenance dose. Frequencies for breakthrough dosing should not exceed the following:
• Oral: every 1 to 2 hours
• Subcutaneous: every 20 to 30 minutes
• Intravenous: every 6 to 20 minutes
• Only short acting opioids should be used for breakthrough pain (e.g., immediate-release morphine, oxycodone, and hydromorphone are common examples).
• Monitor for and appropriately treat common side effects of opioids. Common side effects of opioids include constipation, nausea and vomiting, itching, and transient sedation.
• Because constipation occurs with all chronic opioid therapy, prevention is imperative. Stimulant laxatives (senna or bisacodyl) with or without a stool softener (docusate) are the drugs of choice for opioid-induced constipation.
• Myoclonus, delirium, hallucinations, and hyperalgesia are possible signs of opioid neurotoxicity and require a change in opioid therapy or dose reduction.
• Respiratory depression is very uncommon with appropriate opioid dose titration. However, if it does occur, small doses (0.1 mg) of the mu receptor antagonist, naloxone, are appropriate and can be repeated if necessary. The goal is to increase respirations to a safe level while preventing the patient from experiencing a loss of pain control.
• Fentanyl transdermal patches may be appropriate in some patients however many end-of-life patients experience muscle wasting and dehydration resulting in reduced and variable absorption. Fentanyl transdermal patches have a slow onset of action contributing to difficulty in dose titration.
• Drugs that should not be used for treatment of pain during end-of-life care are listed in Table 4–1.
Table 4–1 Drugs NOT Recommended for Treatment in End-of-Life Care
• Different types of pain may require other analgesics or adjuvant medications. For example:
• Visceral pain (nociceptive pain that is caused by stretching or spasms of visceral organs such as the GI tract, liver, and pancreas) should be treated with the standard WHO step approach to pain, with the addition of anticholinergic agents or, if inflammation is associated with the pain, corticosteroids.
• Bone pain (a common metastatic site of various cancers) is best treated with NSAIDs or corticosteroids in addition to standard opioid therapy.
• Neuropathic pain (pain caused by damage to the afferent nociceptive fibers) can be managed with tricyclic antidepressants, antiepileptic drugs, tramadol, or N-methyl-d-aspartate antagonists such as ketamine. Methadone is an opioid mu agonist that has a role in neuropathic pain given its added N-methyl-D-aspartate antagonist activity.
Terminal Secretions
Palliative Care Considerations
• Terminal secretions, or death rattle, is the noise produced by the oscillatory movements of secretions in the upper airways in association with the inspiratory and expiratory phases of respiration.43,44
• As patients lose their ability to swallow and clear oral secretions, accumulation of mucus results in a rattling or gurgling sound produced by air passing through mucus in the lungs and air passages.
• The sound does not represent any discomfort for the patient. However, the sound is sometimes so distressing to the family that it should be treated.
• Terminal secretions are typically seen only in patients who are obtunded or are too weak to expectorate.
• Drugs that decrease secretions are best initiated at the first sign of death rattle, as they do not affect existing respiratory secretions.
• These agents have limited or no impact when the secretions are secondary to pneumonia or pulmonary edema.
Nonpharmacologic Treatment in Palliative Care
• Position the patient on his/her side or in a semiprone position to help facilitate drainage of secretions.
• If necessary, place the patient in the Trendelenburg position (lowering the head of the bed); this allows fluids to move into the oropharnyx, facilitating an easy removal. Do not maintain this position for long, as there is a risk of aspiration.
• Oropharyngeal suctioning is another option, but may be disturbing to both the patient and visitors.
• Fluid intake can also be decreased, as appropriate.
Pharmacotherapy in Palliative Care
• Anticholinergic drugs remain the standard of therapy for prevention and treatment of terminal secretions due to their ability to effectively dry secretions.45–47
• Drugs used for this indication are similar pharmacologically, and one can be selected by anticholinergic potency, onset of action, route of administration, alertness of patient, and cost.
• The most commonly used anticholinergic agents are atropine, hyoscyamine, scopolamine, and glycopyrrolate.
• Anticholinergic side effects are common and include blurred vision, constipation, urinary retention, confusion, delirium, restlessness, hallucinations, dry mouth, and heart palpitations.
• Unlike the other anticholinergics, glycopyrrolate does not cross the blood–brain barrier and is associated with fewer central nervous system side effects. Glycopyrrolate is a potent drying agent when compared to others agents and has the potential to cause excessive dryness.48
Advanced Heart Failure
Palliative Care Considerations
• Heart failure symptoms at the end of life may include hypotension, volume overload, edema, and fatigue. Patients should be assessed to confirm symptoms are related to heart failure rather than other disease states to ensure appropriate treatment strategies.49,50
• The goals for advanced heart failure treatment will differ from traditional heart failure management. Drug therapy will be focused on symptom management rather than improving mortality. Prevention of cardiovascular disease through cholesterol reduction is no longer necessary at this point.
Nonpharmacologic Treatment in Palliative Care
• Patients should be maintained in a comfortable position with feet elevated to minimize lower leg fluid accumulation.
• Patients should minimize high-salt foods to reduce fluid accumulation associated with a failing heart.
• The patient should not over exert during physical activity. At this stage in heart failure, comfort becomes the primary initiative.
Pharmacotherapy in Palliative Care
• If patient becomes symptomatic of hypotension, reduce dose of angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and/or β-adrenergic blocker. For β-adrenergic blockers, in particular, this should be done gradually to avoid significant clinical deterioration.
• If volume overload occurs or persists, consider tapering off β-adrenergic blocker therapy.
• If the patient is fatigued while taking a β-adrenergic blocking agent and their heart rate does not increase with exertion, consider tapering down the dose of β-adrenergic blocker.
• If patient’s renal function deteriorates (e.g., cardiorenal syndrome), consider discontinuing the ACE inhibitor (or the ARB).
• If the patient restricts sodium and water intake, consider reducing the dose of diuretic or potentially discontinuing therapy.
• Digoxin toxicity is common; therefore, patients should be carefully monitored, and therapy adjusted or discontinued as appropriate. Monitoring should include complaints of anorexia, nausea and vomiting, visual disturbances, disorientation, confusion, or cardiac arrhythmias.
• Hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (and other cholesterol lowering medications) 2 are likely to have a long-term effect rather than a palliative effect; consider discontinuing therapy.
• Figure 4–2 provides a list of agents that improve functional status in advanced heart failure patients.
OUTCOME EVALUATION
Involving the patient and caregivers in the development of the therapeutic plan demonstrates responsible palliative medicine. Before the implementation of drug therapy, the patient and caregiver should be involved with the decision-making process. The practitioner should ensure that his or her understanding of the patient’s goals are being addressed.
Assessing positive therapeutic outcomes includes resolution of symptoms while minimizing adverse drug events. Resolution of symptoms is very important to patients and their caregivers. The hallmark of palliative medicine is specializing in symptom management while preventing adverse drug events. Cultural diversity is an extremely important consideration when establishing goals. Various cultures may perceive some symptoms as more or less important and the practitioner should be aware of those differences.
Nearly all physical symptoms are exacerbated by humanistic suffering. Patients with life-limiting diseases have emotional and spiritual issues that deserve attention by trained professionals. Addressing these concerns and providing support and coping skills can dramatically reduce the medication requirements for symptom control. Psychosocial and spiritual support is not only directed toward the patient in palliative care, but also supports the family during the time of the illness and after the death of their loved one. This bereavement support of the family is mandated under the Medicare Hospice Benefit and is unique to hospice care.
Patient and caregiver education is vital to ensuring positive outcomes. If the patient and caregiver are unaware of the purposes of the strategies used in palliative medicine, adherence to regimens will be hindered and outcomes will be compromised. Practitioners who are challenged in the area of palliative medicine are greatly rewarded through achieving positive outcomes and observing immediate results of good decision making.
Patient Encounter 3
TT, a 76-year-old white female, presents to the outpatient clinic with a complaint of nausea and occasional vomiting. Her nausea started approximately 2 weeks ago and has progressively worsened. The patient also has a recent complaint of constipation (the past few weeks). The patient has a past medical history of non-small cell lung cancer (completed last chemotherapy regimen 3 weeks ago), osteoarthris, and hypertension. The patient has smoked one pack per day for the past 20 years and drinks occasional alcohol. The patient’s family history is unknown. The patient reports an allergy to morphine.
Meds: Naproxen 500 mg every 6 hours as needed for osteoarthritis pain (started 4 weeks ago); enalapril 10 mg twice daily; celecoxib 100 mg twice daily; acetaminophen 500 mg every 6 hours as needed for pain; hydrocodone/acetaminophen 5/500 mg two tablets every 6 hours as needed for cancer pain; ginseng (the patient takes as needed for energy)
What potential drug–drug interactions exist in this patient?
What medications could be discontinued and/or changed?
How does the patient’s allergy to morphine impact potential treatment options?
How could this patient’s pain regimen be improved? Should the different types of pain the patient is experiencing be managed differently?
Patient Care and Monitoring
Other symptoms that are commonly observed in palliative care that the practitioner should monitor:
• Depression: Patients may need to experience quicker symptom relief than typical antidepressants may provide. In some cases, methylphenidate may be an appropriate, short-term option for treatment.
• Insomnia: Many times, patients experience insomnia due to a lack of appropriate symptom management. Treatment should begin with uncontrolled symptoms. Sleep disruption should be minimized and good patient assessment is necessary to effectively manage insomnia.
• Constipation: Most patients experience constipation as a result of opioid use, which requires management with a stimulant laxative; other drugs, poor hydration, dietary supplements, and immobility may contribute to constipation as well. Careful assessment of etiology is important before implementing treatment.
• Diarrhea: Patients experiencing fluid loss through excessive diarrhea need to be monitored for dehydration and electrolyte imbalance. Fluid replacement is typically the first line of therapy in addition to drug therapy to minimize the symptom. Overflow diarrhea from constipation or a bowel obstruction is often misdiagnosed and treated inappropriately, worsening the problem.
• Dysphagia: Difficulty swallowing is common in end-of-life patients and may necessitate that medications be given through alternative routes of administration. Knowledge of drug absorption and disposition when administered rectally, sublingually, and topically is key in good clinical decision making.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. World Health Organization. National Cancer Control Programmes: Policies and Managerial Guidelines, 2nd ed; 2002. www.who.int/cancer/media/en/408.pdf.
2. Higginson I, Astin P, Dolan S. Where do cancer patients die? Ten year trends in place of death of cancer patients in England. Palliat Med 1998;12:353–363.
3. The SUPPORT Principles Investigators. A controlled trial to improve care for seriously ill hospitalized patients: The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). JAMA 1995;274:1591–1598. [Erratum, JAMA, 1996;275:1232.]
4. Billings JA. What is palliative care. J Palliat Med 1998;1:73–81.
5. Higginson I, Astin P, Dolan S. Where do cancer patients die? Ten year trends in place of death of cancer patients in England. Palliat Med 1998;12:353–363.
6. Hill RR. Clinical pharmacy services in a home-based palliative care program. Am J Health Syst Pharm 2007;64:806–810.
7. Lipman AG. Evidence-based palliative care. In: Lipman AG, Jackson KC, Tyler LS, eds. Evidence-Based Symptom Control in Palliative Care: Systemic Reviews and Validated Clinical Practice Guidelines. Binghamton, NY: Hawthorn Press, 2000.
8. Grauer P, Shuster J, Protus BM. Palliative Care Consultant, 3rd ed. Dubuque, IA: Kendall/Hunt Publishing, 2008.
9. Goldstein NE, Fischberg D. Update in palliative medicine. Ann Intern Med 2008;148:135–140.
10. Strickland JM, Huskey AG. Palliative Care. Pharmacotherapy Self-Assessment Program, 5th ed. 2004:191–218.
11. Hospice Care. Health Letter. Harvard Health Publications. July, 2008.
12. Connor SR. Development of hospice and palliative care in the United States. Omega (Westport) 2007–08;56(1);89–99.
13. American Psychiatric Association. Diagnostic and Statistics Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Press, 1994.
14. Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer 1994;30A:1326–1336.
15. Hocking LB, Koenig HG. Anxiety in medically ill older patients: A review and update. Int J Psychiatry Med 1995;25:221–238.
16. Stoudemire A. Epidemiology and psychopharmacology of anxiety in medical patients. J Clin Psychiatry 1996;57(Suppl 7):64–72, 73–75.
17. Rubey RN, Lydiard RB. Pharmacological treatment of anxiety in the medically ill patient. Semin Clin Neuropsychiatry 1999;4:133–147.
18. Grauer PA, Shuster J, Protus BM. Palliative Care Consultant, 3rd ed. Dubuque, IA: Kendall-Hunt, 2008:29–31, 40–47, 78–85.
19. Shuster JL. Confusion, agitation, and delirium at the end-of-life. J Palliat Med 1998;1:177–186.
20. Katz IR. Optimizing atypical antipsychotic treatment strategies in the elderly. J Am Geriatr Soc 2004;52:272–277.
21. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:231–237.
22. Fainsinger R, MacEachern T, Hanson J, et al. Symptom control during the last week of life on a palliative care unit. J Palliat Care 1991; 7:5–11.
23. Tyler LS, Lipman AG. Dyspnea. In: Evidence Based Symptom Control in Palliative Care. Systematic Review and Validated Clinical Practice Guidelines for 15 Common Problems in Patients with Life Limiting Disease, 1st ed. New York: Pharmaceutical Products Press, 2000:109–124.
24. Storey P, Knight CF. UNIPAC Four: Management of Selected Non-Pain Symptoms in the Terminally Ill, 2nd ed. New York: Mary Ann Liebert, 2003;29–35.
25. Thomas JR, vonGunten CF. Management of dyspnea. J Support Oncol 2003;1:23–24.
26. LeGrand SB, Khawam EA, Walsh D, Rivera NI. Opioids, respiratory function, and dyspnea. Am J Hosp Palliat Care 2003;1:57–61.
27. Weissman DE. Fast Facts and Concepts 27: Terminal Dyspnea. November, 2000. End-of-Life Physician Education Resource Center. www.eperc.mcw.edu.
28. Zepetella G. Nebulized morphine in the palliation of dyspnea. Palliat Med 1997;11(4):267–275.
29. Ferraresi V. Inhaled opioids for the treatment of dyspnea. Am J Health Syst Pharm 2005;62:319–320.
30. Emanuel LL, von Gunten CF, Ferris FD, HauserJM, eds. The Education for Physicians on End-of-life Care (EPEC) Curriculum. Module 10: Common Physical Symptoms, 2003:5–10.
31. Kohara H, Ueoka H, Aoe K, et al. Effect of nebulized furosemide in terminally ill cancer patients with dyspnea. J Pain Symptom Manage 2003;26:962–967.
32. Shimoyama N, Shimoyama M. Nebulized furosemide as a novel treatment for dyspnea in terminal cancer patients. J Pain Symptom Manage 2002;23:73–76.
33. Stone P, Kurowska A. Re: Nebulized furosemide for dyspnea in terminal cancer patients. J Pain Symptom Manage 2002;24:274–275.
34. Bruera E, Sweeney C. In: Principles & Practices of Palliative Care & Supportive Oncology, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2002:Ch 14.
35. Ferris FD, von Gunten CF, Emanuel LL. Ensuring competency in end-of-life care: Controlling symptoms. BMC Palliat Care 2002;1:5.
36. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999;17:2971–2994.
37. Tyler LS. Nausea and vomiting in palliative care. In: Evidence Based Symptom Control in Palliative Care. Binghamton, NY: The Haworth Press, 2000:163–181.
38. Vella-Brincat J, Macleod AD. Haloperidol in palliative care. Palliat Med 2004;18:195–201.
39. Study to understand prognoses and preferences for outcomes and risks of treatment (SUPPORT). JAMA 1995;274:1591–1598.
40. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer pain, 5th ed. Glenview, IL: American Pain Society, 2003.
41. Berger AM, Portenoy RK, Weissman DE. Principles and Practice of Palliative Care and Supportive Oncology, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2002.
42. McCaffery M, Pasero C. Pain: Clinical Manual, 2nd ed. St. Louis: Elsevier Mosby, 1999.
43. Wildiers H, Menten J. Death rattle: Prevalence, prevention and treatment. J Pain Symptom Manage 2002;34:310–317.
44. Morita T, Tsunoda J, Inone S, Chihara S. Risk factors for death rattle in terminally ill cancer patients: A prospective exploratory study. Palliat Med 2000;14:19–23.
45. Bennett M, Lucas V, Brennan M, Hughes A, O’Donnell V, Wee B. Using anti-muscarinic drugs in the management of death rattle: Evidence-Based guidelines for palliative care. Palliat Med 2002;16:369–374.
46. Varkey B. Palliative care for end-stage lung disease patients. Clin Pulm Med 2003;10(5):269–277.
47. Hyson HC, Johnson AM, Jog MS. Sublingual atropine for sialorrhea secondary to parkinsonism: A pilot study. Mov Disorder 2002;17(6):1318–1320.
48. Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle. Palliat Med 2001 July 1;15(4):329–336.
49. Hauptman PJ, Havranek EP. Integrating palliative care into heart failure care. Arch Intern Med 2005;165: 374–378.
50. McPherson ML. Palliative Care and Appropriate Medication Use in End-Stage Heart Failure. Medscape Nurses. 2007, www.medscape.com