I. Problem/Challenge.

To address non-pain symptoms in palliative care patients

This chapter outlines how to develop a systematic approach to a patient with serious illness who has an uncontrolled symptom, by working to identify the underlying cause of the symptom and then to develop a treatment approach based on the cause.

This section will approach common non-pain symptoms that may arise in hospitalized patients with life-limiting illness on a general medicine service. We use the term life-limiting illness in this section to identify the patient in whom palliative approaches may be indicated, as the patient approaches the end-of-life.

The goal of symptom management includes considering what might be the cause of the symptom itself, or its differential diagnosis, followed by treatment approaches which would be tailored to the underlying cause. As such, this discussion will not be exhaustive of all possible symptoms or causes, but will demonstrate an approach to several common symptoms experienced at the end-of-life.

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One challenge in symptom management is the lack of clear evidence for some frequently used interventions. When data is not available for this specific population, consensus opinion of expert panels has been the prevailing method of determining how to manage patients’ symptoms.

Please note that some of these diagnostic approaches and treatment options could be applied to patients without life-limiting illness, but the treatment approaches should be used with caution in cases not relating to the end-of-life patient care. However, the approach of searching for an underlying etiology of a given symptom and attempting to alleviate that symptom can and should be applied to a broader population of general medicine inpatients.

This section will focus on the following combinations of symptoms:

  • 1. Nausea/vomiting/constipation

  • 2. Dyspnea/shortness of breath/anxiety

  • 3. Fatigue/muscle weakness

  • 4. Insomnia

II. Identify the Goal Behavior:

A comprehensive approach to non-pain palliative care symptoms

Goal behavior relating to the management of non-pain symptoms in life-limiting illness:

Step 1. Identify symptoms which may be amenable to tailored management, including as dyspnea, anxiety, shortness of breath, nausea and vomiting, constipation, or fatigue and insomnia.

Step 2. Develop an approach to address a symptom by working to understand the differential diagnosis of the underlying potential causes of the symptom.

Step 3. Identify treatment options based on the identification of the underlying cause of a given symptom.

Step 4. When a symptom management approach is challenging to develop, know that palliative care consultation can be sought to assist with developing a more advanced symptom management approach.

III. Describe a Step-by-Step approach/method to this problem.

A 4-Step systematic approach to non-pain symptom management in life-limiting illness

This chapter covers several common symptoms, including nausea and vomiting, constipation, anxiety and shortness of breath, fatigue and weakness, as well as insomnia. In all cases, the management of these symptoms involves determining the underlying cause and directing therapy at the underlying pathophysiology. Symptom management can be challenging, and the co-management or consultation support of a palliative care team may be integral in those cases, to achieving symptom control.

A. Nausea/vomiting/constipation:

Step 1. Identify and classify the nausea and vomiting, as well as constipation:

Nausea and vomiting can occur due to a variety of pathophysiologic causes. The vomiting reflex is activated by a cluster of neurons in the medulla known as the vomiting center. The sources of input from to the medullary vomiting center include the cerebral cortex, sensory organs and the vestibular apparatus in the inner ear. There can also be an indirect stimulation of the medullary vomiting center by the chemoreceptor trigger zone in the floor of the fourth ventricle. These pathways are theorized to be linked to different neurotransmitters, and guide the associated approaches to therapy.

Constipation is a decrease in frequency of bowel movements, and can result from a variety of factors. Constipation can be associated with nausea and vomiting, especially if the process has progressed to a point of bowel obstruction. Bowel habits can change in the setting of factors including metabolic or hormonal derangements, medications which affect motility, dehydration, or decreased dietary fiber.

Step 2. Figure out the ‘why’ or differential diagnosis of nausea and vomiting, which includes constipation:

The key lies in the history and physical of the patient who reports nausea and vomiting. Key questions to ask include eliciting anxiety or anticipation, which have been shown to heighten nausea, medications, constipation or the evolution to bowel obstruction mediated by bowel distension, heartburn or other symptoms which may suggest gastritis, symptoms which suggest vestibular irritation, or the presence of toxins such as uremia or metabolic disturbances such as hypercalcemia. Increased intracranial pressure can also result in the sensation of nausea. Of note, many pain medications used in palliation of pain symptoms can result in nausea, as well as constipation.

Pathophysiologic pathways have been hypothesized for the majority of potential causes of nausea, and are often linked to a neurohormonal pathway. The causes of nausea can also be grouped into the following categories:

  • – Cortical/CNS issues: Increased intracranial pressure, anxiety, CNS tumor, or potentially uncontrolled pain

  • – Vestibular or middle ear issues: Acute vestibular neuronitis, motion sickness, middle ear infections.

  • – Chemoreceptor trigger zone activation/Metabolic derangements: These are very common causes of nausea in the palliative care patient. Causes include medications (including opiates, antibiotics, and chemotherapy), renal or liver failure, hyponatremia, or hypercalcemia.

  • – Visceral or abdominal tract issues: Constipation, gastroparesis or ileus causing bowel distension, gastritis, GERD, or potentially gag reflex from instrumentation or nasogastric or dobhoff tubes, or potentially irritation by medications including NSAIDs, antibiotics, or vitamins.

Step 3. Find treatment options, based on theory on the cause of nausea and vomiting or constipation:

Cortical/CNS issues:

  • – If suspect increased intracranial pressure or CNS tumor, suggest urgent involvement of a neurologist or neuro-oncologist if available. Steroids may be indicated, in particular, but should be administered as urgent consultation and imaging are obtained. In some cases, this may involve transfer to a center with the necessary services.

  • – If there is suspicion for anxiety leading to nausea, benzodiazepines may be useful, as well as social work and supportive counseling.

  • – Uncontrolled pain may result in nausea, in which case, eliciting a history of pain and treating the pain itself with opiates or other appropriate pain medications may be sufficient to treat the superimposed nausea.

Vestibular or middle ear issues:

  • – If acute vestibular disease is suspected, meclizine 25mg orally twice daily may be indicated. Often dehydration has also occurred in the setting of nausea and vomiting, and supportive care may be indicated.

  • – Middle ear infections may be present, as indicated by a bulging tympanic membrane, in which case antibiotics and decongestants may be indicated, depending on the clinical scenario.

  • – Motion sickness may be treated with scopolamine or diphenhydrinate.

Chemoreceptor trigger zone activation/Metabolic derangements:

  • – If suspect medications may be causing the nausea, such as opiates or antibiotics, would attempt to switch medications or adjust dose.

  • – If suspect renal or liver disease, sub-specialty consultation may be indicated to assist with symptom management. In general, haloperidol can be effective for palliation, but should be used with caution due to limited clearance.

  • – Hyponatremia and hypercalcemia should be treated as indicated by their underlying cause, as noted in their individual chapters.

Visceral or abdominal tract issues:

  • – If constipation is present, it is important to assess for signs or symptoms of bowel obstruction. This will help determine the appropriate treatment for constipation, and if severe, laxatives and treatments from the oral route should be held until the obstruction is relieved. Laxatives and stool softeners should be used in particular in those patients receiving opiates, given the high associated constipation risk.

  • – Nausea may be caused by gastritis in the absence of heartburn symptoms, and if suspected, should be treated appropriately, including acid-suppression therapy.

  • – In cases of GI malignancies or severe visceral distension, palliative care consultation may be indicated to assist with choice of agent and to consider palliative measures to relieve nausea and vomiting.

Step 4. Examples when consultation or assistance from palliative care teams may be indicated:

  • – Intractable nausea and vomiting, despite appropriate initial treatment

  • – Challenging treatment options when the patient is hoping to transition out of the hospital but cannot take adequate oral medications.

  • – Obstipation despite oral or rectal agents

  • – Constipation not responsive to typical agents, particularly in setting of high-dose opiates.

For more detail see references in What’s the evidence? section.

B. Dyspnea/shortness of breath/anxiety:

Step 1. Identify and classify the shortness of breath or anxiety:

Dyspnea of shortness of breath: Dyspnea can be defined as a sensation of uncomfortable breathing, and can occur due to increased ventilatory demand, chemoreceptors sensing increased carbon dioxide or hypoxemia, or in response to fluid or microemboli in capillaries and alveoli. The end result of dyspnea is both common and can be very distressing to patients and their families.

Anxiety: Patients with life-limiting illness may experience varying degrees of anxiety, and may report a variety of symptoms including shortness of breath, palpitations, anxiety itself, or insomnia. Patients may not recognize that they are experiencing anxiety. As with other symptoms, determining the underlying issue will be critical.

Step 2. Figure out the ‘why’ or differential diagnosis of dyspnea or shortness of breath, which can present similarly to anxiety:

Shortness of breath:Dyspnea can occur by several mechanisms related to chemoreceptors for oxygen and carbon dioxide exchange, as well as mechanoreceptors for stretch in airways, lungs, and the chest wall, or receptors at the capillary and alveolar level sensing fluid in the alveoli or microemboli. These mechanisms can result in a mismatch between the brain’s perception of ventilation and the actual air flow and oxygen and carbon dioxide levels the body is experiencing. The dyspnea may abate when the patient’s partial pressure of oxygen rises rapidly, or exceeds 75mmHg, and the patient may then become more somnolent.

  • – Begin with the history and physical: Common medical causes of shortness of breath in life-limiting disease include pleural effusions, pericardial effusions and tamponade, decompensated heart failure, superior vena cava syndrome in patients with lung cancer or lymphoma, ascites, or anemia.

  • – Perform appropriate testing: A chest radiograph can be used to evaluate for pulmonary edema and pleural effusions. A set of blood work including a complete blood count and basic chemistries may indicate severe anemia, or contributing electrolyte or acid-base disturbances. Pulse oximetry can identify the presence of hypoxemia, and further investigation into the cause of the hypoxemia can proceed. Once these underlying potential medical causes of dyspnea have been elucidated, treatment can be tailored to both treat the sensation of dyspnea, as well as the specific medical causes which can be treated as indicated with palliative approaches.

Anxiety:

  • – Begin with the history: As with other symptoms, the patient’s medical and psychiatric history can provide keys to the current anxiety that the patient may be experiencing.

  • – Consider social work or palliative care consultation: The assistance of a multidisciplinary team including a social worker, chaplain and/or palliative care clinician can be instrumental in elucidating the factors in the patient’s experience leading to their anxiety.

  • – Look for underlying medical condition or medication which may be causing anxiety: Many medical conditions can also present as anxiety, including shortness of breath as noted, as well as angina pectoris, decompensated heart failure, electrolyte disturbances including calcium and potassium, encephalopathy, underlying reactive airway disease, alcohol or benzodiazepine withdrawal syndromes, as well as a variety of medications from glucocorticoids through beta-adrenergic agonists and anti-emetics which can cause akathisia. A palliative care consultation may be useful in identifying patient-specific factors.

Step 3. Find treatment options, based on assessed causes of shortness of breath or anxiety:

Options to treat shortness of breath:

  • – In about 1/4 of cases, no specific reversible cause of dyspnea is identified. Anxiety and muscle weakness may play some role in these cases. General symptomatic treatment with opiates or benzodiazepines may be helpful for these patients, as well as for those where an underlying medical cause is identified.

  • – Medications which address the symptom of shortness of breath without addressing the underlying cause, commonly include opiates and benzodiazepines. Benzodiazepines can be particularly useful in the patient who is experiencing associated anxiety with their dyspnea. These medications should be used for patients with life-limiting illness for shortness of breath, and palliative care consultation can be sought for assistance in determining the indication for adjusting doses and changing agents.

In general, a starting dose for lorazepam for the anxious dyspneic patient is 0.5 – 1.0 mg every 4 to 6 hours orally or clonazepam 0.5 to 1.0 mg at bedtime orally. Oral or intravenous opiates can be useful for the very short of breath patient, with morphine as an intravenous option from 1mg to 5mg as a potential starting dose. These medications should be used with caution, and patients and families should be notified when a new agent is started, as well as the potential side effects of these medications which might be expected. Sedation and encephalopathy are risks with both classes of medications, and dose reductions, changing the agent, or cessation of these agents should be considered if either occurs.

  • – Once an underlying medical cause of shortness of breath is identified, efforts to palliate that condition may be considered. The primary goal can be to determine if the identified medical condition is able to be addressed in a palliative approach that is in keeping with the patient and family’s wishes, and that any discomfort will be outweighed by short term improvements in the dyspnea. This discussion can be facilitated through a palliative care team.

  • – In the case of a pleural effusion, a pulmonary or interventional pulmonary consultation may be obtained to consider the options to address the effusion.

  • – In the case of decompensated heart failure, or other cardiac conditions, tailored treatment can be considered to address the patient’s symptoms.

  • – When bronchospasm or reactive airway disease is suspected, inhaled bronchodilators or in some cases glucocorticoids can be useful to address the bronchospasm, as part of a comprehensive treatment plan.

  • – Supplemental oxygen therapy is indicated when patients are hypoxemic on oximetry. It has not been shown to improve the sensation of dyspnea when hypoxemia is not present.

  • – Palliative care clinicians may be useful to the hospitalist in these cases, to assist in helping the patient and family take part in the decision-making process and determine what palliative treatments will be in keeping with their overall wishes and goals of care.

Options to treat anxiety:

  • – If an underlying psychiatric or emotional cause of the anxiety is determined, psychiatric liaison consultation or social work consultation may be indicated.

  • – If short-acting treatment options are desired, the same doses of benzodiazepines used in the dyspneic patient may be useful. In general, a starting dose for lorazepam for the anxious dyspneic patient is 0.5 – 1.0 mg every 4 to 6 hours orally or clonazepam 0.5 to 1.0 mg at bedtime orally.

  • – For more sustained therapy, selective serotonin reuptake inhibitors (SSRIs) may be useful, as well as consideration of psychiatric consultation to assist in determining if comorbid depression is present.

Step 4. Examples when consultation or assistance from palliative care teams may be indicated:

– If a condition is identified, such as a malignant pleural effusion, which may be contributing to shortness of breath and might be amenable to a palliative procedure, for example, a thoracentesis or a pleurX catheter. May be helpful to involve interventional pulmonary team, as well as palliative care.

  • – In the case of pulmonary disease with airway obstruction, particularly in the setting of lung malignancies, consultation with interventional pulmonary consultants may be indicated to consider if palliative stenting or other procedures to address the obstruction were an option.

  • – In terms of anxiety, if it were determined that the cause were not related to underlying shortness of breath, some patients may benefit from inpatient psychiatric liaison consultation to assist acute management of anxiety. Other patients may find social work consultation useful in developing coping strategies and identifying underlying factors which may be contributing to the observed anxiety.

  • – Depression may be difficult to diagnose in a cancer patient, as many patients are experiencing sleep disturbances, anorexia, weight loss or fatigue. A psychiatric or palliative care consultation can be useful to assist in management of these patients in whom depression and anxiety are suspected.

For more detail see references in What’s the evidence? section.

C. Fatigue/Muscle weakness:

Step 1. Identify and classify the reported fatigue or muscle weakness:

Fatigue has been defined by the National Comprehensive Cancer Network (NCCN) as a sense of subjective tiredness that persists and affects functioning, and can be related to cancer or cancer treatment. While this definition is aimed at cancer patients, the description can plausibly be found associated with other medical conditions at the end of life. As with other symptoms, fatigue or weakness can be associated with other underlying medical conditions or untreated non-pain or pain symptoms.

Step 2. Figure out the ‘why’ or differential diagnosis of fatigue or muscle weakness:

Evaluate for the presence of pain, anxiety, depression, or insomnia in patients who report or are found to have fatigue. These symptoms can be addressed as indicated.

Identify causes of fatigue in the medical patient, which can be specifically found in the patient with life-limiting illness. Common causes include anemia, renal failure, electrolyte abnormalities including hypocalcemia or hypercalcemia, hypokalemia or hyponatremia, anorexia with or without depression, and hypoglycemia.

In rare cases of patients with lung cancer, Lambert-Eaton Syndrome may be the cause of fatigue. This syndrome, of which the hallmark is a reverse of the typical myasthenic experience, where symptoms improve and the patient gets stronger with repetitions, should be diagnosed with the assistance of a neurologist and oncologist. Treatment in this case is associated with both addressing the malignancy and the associated neurologic complications.

Step 3. Find treatment options, based on theory on the cause of fatigue or muscle weakness:

In patients in whom a medical cause may be contributing to their fatigue, as noted above, treatment should be focused at the underlying condition. This can include repletion of electrolytes or the associated endocrine condition, or transfusion if indicated for anemia.

If no underlying reversible condition is identified, and no other contraindications exist, methylphenidate can be considered as therapy for fatigue in the patient with life-limiting illness. This should be initiated in concert with a palliative care clinician’s assistance in monitoring the dose and side effect profile.

Step 4. Examples when consultation or assistance from palliative care teams may be indicated:

Palliative care consultation may be indicated when initiating methylphenidate therapy for fatigue, or if the differential diagnosis for a given patient proves difficult.

Discussion with the patient’s oncologist, in the case of cancer patients, may be helpful to determine if fatigue is expected either with ongoing treatment or as a result of the underlying malignancy.

For more detail see references in the What’s the evidence? section.

D. Insomnia

Step 1. Identify and classify the insomnia:

Insomnia can be defined as either a difficulty falling asleep, commonly taking more than 30 minutes, or a difficulty staying asleep, sleeping less than 85% of the time spent in bed trying to sleep. This issue should occur at least three times a week, and affect the patient’s daytime functioning. For the hospitalized patient, transient insomnia is also a possibility, which can last for one month or less and be exacerbated by hospitalization.

Patients and their families can both be distressed by the lack of sleep, as well as the impact on other symptoms including pain and contribution to a depressed mood.

Step 2. Figure out the ‘why’ or differential diagnosis of the causes of insomnia:

Insomnia can occur as a result of previously discussed symptoms including pain, nausea and vomiting, anxiety, dyspnea and in particular nighttime hypoxemia and paroxysmal dyspnea, as well as encephalopathy or other sleep-wake cycle disturbances.

Medications used to treat the symptoms discussed in this section can also lead to insomnia, including anti-emetics, opiates, benzodiazepines, as well as corticosteroids or glucocorticoids.

Underlying medical conditions such as anemia, which can also be associated with restless leg symptoms, can also contribute to sleep disturbances.

Dietary intake of alcohol or caffeine, as in patients without life-limiting illness, can also contribute to sleep disturbances in these patients.

Step 3. Find treatment options, based on theory on the cause of the insomnia:

As with other symptoms, the primary goal is to identify a reversible psychiatric or other medical condition which might be contributing to the insomnia.

If this approach is ineffective, medications typically used for insomnia could be used. Benzodiazepines, antidepressants, and zolpidem have been shown to have some effectiveness in patients with life-limiting illness. Clonazepam 0.5 – 1.0mg orally at bedtime would be an appropriate benzodiazepine choice, while oral zolpidem 5 to 10mg at bedtime or trazodone 50 – 100mg could be considered as well. Consideration for renal and hepatic clearance in a patient with life-limiting illness, and appropriate adjustments in dose based on related impairments, should be made with the assistance of the inpatient pharmacist.

For patients in whom night-time encephalopathic symptoms or delirium are contributing to their sleep disturbances, oral quetiapine at 25 – 50mg may prove useful.

Step 4. Examples when consultation or assistance from palliative care teams may be indicated:

– If on depression and anxiety screening, an acute psychiatric illness or emergency is suspected, consultation with the inpatient psychiatry team may be indicated. As noted earlier, symptoms typical of depression such as anorexia, weight loss, or fatigue and sleep disturbances may be related to the underlying life-limiting illness.

– In some cases, social work consultation may be indicated if social or other stressors are playing a role in the patient’s experience. Social work consultation may also be sought for emotional support or assistance with coping.

For more detail see references in What’s the evidence? section.

IV. Common Pitfalls.

Common Pitfalls in Symptom Management of Non-Pain Symptoms in Life-limiting Illness:

Missed opportunities to address symptoms: A key opportunity to improve the symptom management approach is to work to identify those patients who have uncontrolled symptoms, and to find opportunities to alleviate their symptoms. It would be ideal if the patient could directly communicate their symptoms to the appropriate provider. In some cases, the patient cannot directly communicate their symptoms, or may not be able to effectively express their concerns. In these cases, it can be helpful to speak with the other members of the inpatient care team, as well as family members, to elicit anything they have noticed or that the patient may have mentioned to them in passing.

‘Covering’ symptoms with medications without first approaching the underlying cause: Starting symptom management treatments without knowing the cause of the symptom is a common pitfall. As discussed in this section, there are a variety of treatment approaches to several common symptoms such as nausea or fatigue and weakness. An attempt to discern the underlying cause of a given symptom will enhance the chances of alleviating that symptom.

When ‘as needed’ orprn medications are not actually administered: After taking the time to ensure that the patient has an appropriate medication regimen available to address his or her symptoms, the next step should be to ensure that both the patient and family, as well as the clinical care team are aware of the treatment regimen. Checking with the patient and care team on a daily basis to ensure that the regimen is meeting the patient’s symptom needs, and that the patient is able to request the medications when the symptoms arise.

V. National Standards, Core Indicators and Quality Measures.

American Society of Clinical Oncology (ASCO) guidelines for Supportive Care and Quality of Life:

Accessed on January 5, 2013 via:http://www.asco.org/ASCOv2/Practice+%26+Guidelines/Guidelines/Clinical+Practice+Guidelines/Supportive+Care+and+Quality+of+Life?dateFilter=All

This repository of guidelines includes specific guidelines for a variety of aspects of caring for the cancer patient.

National Comprehensive Cancer Network (NCCN) Guidelines for for anti-emetic therapies (subscription required to view specific guidelines)

National Consensus Project for Quality in Pallative Care, Palliative Care Algorithm

Formal reference: National Consensus Project for Quality Palliative Care (2009). Clinical Practice Guidelines for Quality Palliative Care, Second Edition.http://www.nationalconsensusproject.org

or via:http://www.nationalconsensusproject.org/Guidelines_Download2.aspx

VI. What's the evidence?

Nausea/Vomiting/Constipation:

Wood, GJ. ” Management of Intractable Nausea and Vomiting in Patients at the End of Life”. JAMA.. vol. 298. 2007. pp. 1196-1207.

Janet, Abrahm. “A physician's guide to pain and symptom management in cancer patients.”. pp. 339-340.

“UNIPAC 3rd Edition (Palliative Care Review Series), Book U4,”. pp. 35-47. American Society of Clinical Oncology (ASCO) Guidelines for Antiemetics use accessed on January 5th, 2013, via:http://www.asco.org/ASCOv2/Practice+%26+Guidelines/Guidelines/Clinical+Practice+Guidelines/Antiemetics%3A+American+Society+of+Clinical+Oncology+Clinical+Practice+Guideline+Update

Luce, JM, Luce., JA. “Management of Dyspnea in Patients with Far-Advanced Lung Disease”. JAMA.. vol. 285. 2001. pp. 1331-1337.

Janet, Abrahm, MD.. “A physician's guide to pain and symptom management in cancer patients.”. pp. 319-330.

Yennurajalingham, S. “Palliative Management of Fatigue at the Close of Life”. JAMA.. vol. 297. 2007. pp. 295-304.

Janet Abrahm, MD. “A physician's guide to pain and symptom management in cancer patients”. pp. 367-372.

Kupfer, DJ. “Reynolds CF. Management of Insomnia”. NEJM. vol. 348. 1997. pp. 341-346.

Janet Abrahm, MD. “A physician's guide to pain and symptom management in cancer patients”. pp. 364-366.

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