This chapter will focus on basic methods of treating the suffering and distress caused by common pulmonary symptoms in AIDS patients. The approaches offered below are useful in relieving discomfort, even when the underlying disease is not treatable. The first part of this chapter will explore issues related to end-of-life decisions in the care of patients who have pulmonary diseases. The second part will address treatment for specific pulmonary symptoms.
HIV-positive individuals are at risk for a variety of disease processes that compromise lung function or cause respiratory symptoms (see Table 6-1, PDF). In fact, pulmonary manifestations of AIDS are among the most frequent causes of death in HIV disease. Symptoms associated with lung involvement can be very disturbing to patients. When symptoms include severe air hunger or even a sensation of suffocation, these can lead to escalating feelings of fear, anxiety, and panic. Relief of symptoms can make a great deal of difference in the quality of life for people with HIV, even when the underlying disease is progressing.
In July of 1981, Morbidity and Mortality Weekly Report (MMWR) described five cases of Pneumocystis carinii pneumonia (PCP) in homosexual men. Since that time PCP has become the most common AIDS-defining condition. Even in the era of HAART (highly active antiretroviral therapy), PCP remains a frequent opportunistic infection affecting people who are not yet in care or who are unable to adhere to prophylaxis or treatment regimens.1
Although the overall incidence of PCP has decreased, people still die of Pneumoncystis, particularly when the organism becomes resistant to available therapies. Current PCP treatment consists of sulfamethoxazole/trimethoprim, pentamidine, atovaquone or methotrexate, depending on the degree of resistance, although toxicities may limit the usefulness of these drugs. Corticosteroid therapy (40 mg of prednisone daily) is recommended to control symptoms for patients with moderate to severe disease or compromised gas exchange evidenced by hypoxemia (pulse oximetry <88%). If antibiotics are used, prednisone may be tapered over the course of treatment.
While the frequency of PCP infections has decreased in recent years, other forms of pulmonary disease, such as bacterial pneumonias and non-Hodgkin's lymphoma, have become more prevalent in AIDS patients.2 Recurrent bacterial pneumonia with bacteremia is frequent, especially in patients with a history of injection drug use. Streptococcus pneumoniae is the responsible organism in 20 to 70% of cases; Pseudomonas aeruginosa is also common and associated with increased rates of bacteremia and death.3 Even when treated vigorously these infections may exacerbate the progression of HIV disease.4
Palliative Pulmonology and End of Life Issues
Use of Oxygen in Terminal Care
Adequate oxygenation is essential to maintain normal cellular function, but information about the specific effects of mild to moderate hypoxemia in terminally ill patients is limited. As patients approach the final stages of life, supplemental oxygen may be beneficial in some settings. For example, oxygen may be useful in reducing cognitive deficits associated with hypoxemia. It is often assumed that oxygen may reduce the sensation of dyspnea, but the evidence does not consistently support this.5
Oxygen would be expected to be therapeutic if hypoxemia is stimulating increased respiratory effort and contributing to fatigue. However, the frequency with which this occurs is not clear since some studies have shown that even moderate hypoxemia does not significantly increase ventilation.6 In addition, there is a great deal of individual variation in the response of the respiratory drive to hypoxemia and, under most circumstances, carbon dioxide tension in the blood plays a greater role than oxygen in regulating respiratory rate and volume. Thus, in some patients, hypoxemia probably does not produce noticeable symptoms, particularly if mental function is already declining from progressive disease.
Even in healthy individuals, hypoxemia is not necessarily uncomfortable and may produce symptoms similar to inebriation. In exercises with Air Force flight crews in altitude chambers, most of the participants initially were unable to determine when they were significantly hypoxemic. In fact, though they perceived no changes, they were often surprised to discover that they had decreased color vision, impaired mental acuity, and slower reflexes by the time they responded to instructions to put on oxygen masks. It was only after restoring normal oxygen levels that they recognized the contrasts in vision, hearing, and perception. When these individuals were subsequently re-exposed to the altitude chamber, many found that their previous experiences did not improve their ability to recognize signs of hypoxemia in themselves. (Griffin R, retired flight surgeon and Colonel, USAFR. Telephone communication with author, April, 2002.)
During the final days or hours of life, AIDS patients, especially those with pulmonary disorders, are likely to become increasingly hypoxemic. They may be unaware of any associated symptoms and may resist efforts to improve oxygenation by removing a mask or nasal cannula. Simple or non-rebreathing masks may create feelings of claustrophobia and anxiety. In these settings, administration of oxygen may not be a comfort measure, although in some situations it may be life-prolonging. If prolonging life is no longer a goal of the patient, family, or friends, or if life-prolonging measures are now compromising comfort, it may be appropriate to consider discontinuing supplemental oxygen. This can be done by not replacing oxygen delivery devices when removed by the patient or by titrating oxygen flows downward and then discontinuing supplemental oxygen over a matter of minutes or hours. Oxygen can always be restarted if the patient appears to have increased symptoms or discomfort associated with stopping oxygen. In most cases this is not necessary.
Use of Antibiotics in Terminal Care
While we have made remarkable progress in increasing life expectancy by combating infectious diseases over the last one hundred years, there still may be wisdom in the old saying "pneumonia is the old man's friend." Death from infection, particularly if the patient is dehydrated, debilitated, and immunocompromised, can be rapid and peaceful. Dyspnea is likely to be minimal when dehydration limits fluid accumulation in the infected lung and/or the inflammatory response is impaired. Pain and cough usually can be managed successfully with opioids.
Likewise, with effective palliation of symptoms, central nervous system infections such as toxoplasmosis, bacteremia, or intra-abdominal sepsis may help to prevent a prolonged or difficult dying process in end-stage patients. In these situations it may not be in a patient's best interest to pursue aggressive treatment of infections, even though it may be relatively easy to do so.
Infections that are not life-threatening but do contribute to discomfort can always be treated with the appropriate antibiotics. For example, bronchitis or urinary tract infections can cause distressing symptoms that respond well to antibiotic treatment. But in the terminal phases of illness, symptomatic relief of life-threatening infections may be all that is needed. Prednisone may be adequate to combat the symptoms of Pneumocystis carinii pneumonia, and low doses of opioids may be enough to control the distressing symptoms of bacterial pneumonia.
The Role of Fluids and Dehydration in Terminal Care
Decreased fluid intake is a normal part of the dying process and can lead to profound dehydration. There is some evidence that complaints of dry mouth are no greater in dehydrated patients than in patients receiving hydration during the final stages of life, perhaps because of increased mouth-breathing in both groups.
If symptoms of oral dryness are well controlled, dehydration can actually provide several benefits to people in the final days of life. First, dehydration decreases symptoms from pulmonary infections. With a decrease in total body water there is less interstitial or alveolar fluid associated with the inflammatory response to an infection. This leads to a reduction in symptoms including hypoxemia, coughing, shortness of breath, and secretion production. Second, decreased intravascular fluid may reduce pulmonary symptoms from heart failure by lowering preload and the hydrostatic pressure driving fluid into the lungs. Third, dehydration may lead to a reduction in secretion volume, which can reduce coughing and associated fatigue in a severely debilitated patient and may help control the terminal sounds ("death rattle") from accumulated airway secretions in a dying patient.
On the other hand, in some situations fluids may be beneficial. For example, thick, dry secretions may be deleterious for a patient who has an effective cough and is not imminently dying. In this situation, careful systemic hydration may promote comfort by allowing easier clearance of airway secretions. Nebulized saline has been used to humidify airways, but is less effective than systemic fluids for thinning secretions and can irritate the airways.
For some terminal patients, partial rehydration may reduce agitation or restlessness. Parenteral fluids also may be appropriate for the dehydrated patient who seeks to prolong life or enhance a sense of well-being in order to achieve specific short term goals. However, when a patient has completed the work of preparing for death, intravenous fluid administration may be less desirable, because it can prolong the dying process and/or increase the discomfort associated with it.
Use of Opioids and Risks of Respiratory Depression
Concerns about respiratory depression have sometimes limited the use of opioids in the past, even in the presence of significant symptoms. Current evidence indicates that as long as opioids are very carefully titrated against symptoms of real pain or dyspnea, respiratory depression does not present a serious danger.7
It appears that pain itself opposes the respiratory depressant effect of the narcotics, although the mechanism for this is not known. This idea is supported by the observation that patients who undergo procedures such as nerve blocks to relieve pain may experience respiratory depression afterward on the same doses of medication that had no negative impact on respiration prior to the procedure.7 It has also been found that arterial carbon dioxide tension, a sensitive measure of ventilation, remained in the normal range over a wide variety of plasma opioid concentrations in seriously ill patients with COPD or bronchogenic cancer.8 It is likely that the risk of respiratory depression increases if opioid doses are raised rapidly or are given in excess of the dose needed to control symptoms.
When opioids are used for treatment of dyspnea, rather than pain, there is probably more risk of respiratory depression, although opioids can easily be used safely in this setting. To avoid adverse effects, it is again helpful to titrate doses carefully against the patient's reported symptoms. In this case, the symptom is the patient's perception of dyspnea -- not an increased respiratory rate or effort. If tachypnea is felt to reflect a component of anxiety, fear, or stress, those symptoms can be treated with lorazepam.
In many situations, an elevated respiratory rate may not be especially uncomfortable for the patient, and in some settings can represent a physiologic adaptation to maintain adequate ventilation. If this is the case, a reduced respiratory rate is not a good indicator of effective palliation. Life-threatening respiratory depression and breathing patterns that closely resemble agonal respiration can develop if excessive doses of opioids are used to reduce respiratory effort. Since dying patients can have respiratory rates as low as 6 to 10 breaths/min,9 it is important to monitor changes in respiratory rate, as well as the actual rate.
The ethical principle of double effect is frequently invoked when symptom management requires such large doses of medication that there is a significant risk of hastening death. It is generally accepted that as long as the primary intention is to treat symptoms and provide comfort, the medication is justified, regardless of unintended consequences such as shortening life. The principle of double effect would seem to apply as long as careful attention is given to titrating medications against specific patient-identified symptoms to determine the smallest dose needed to prevent distress. Titration against symptoms, rather than the use of standard dosing formulas, helps to adjust for individual variation in opioid needs, metabolism, and tolerance. The focus of treatment should be on the patient's perception of discomfort, not just on signs that may be disturbing to the health care providers.
Use of Ventilators and Bilevel Positive Airway Pressure in Terminal Care
Mechanical support of respiration may be very helpful for patients who have respiratory failure from a disease process that is likely to be reversible. In these patients, weaning from the ventilator is usually accomplished uneventfully, once the underlying cause of respiratory compromise has been treated. The decision to use mechanical ventilation is much more difficult in patients with end-stage disease such as visceral Kaposi's sarcoma or resistant PCP where the potential for weaning is in serious doubt.
The complexity of these decisions is illustrated by the following information about outcomes in ventilated AIDS patients. A summary of seven studies done on AIDS patients between 1987 and 1994 revealed survival rates (discharge from the hospital) of 11% to 31% in patients who required mechanical ventilation for PCP. In other studies, mortality was strongly associated with a CD4 count < 50/mm3 (94%), the development of pneumothorax (100%), failure to respond to PCP treatment before intubation (80 to 90%), and ventilation for longer than two weeks.10
To identify appropriate interventions, health care practitioners must understand carefully the patient's specific goals, which may change over time as the disease progresses. If lung failure is likely to be irreversible, mechanical ventilation should be undertaken only if prolonging life meets specific needs or desires of the patient. In most cases of irreversible lung failure, mechanical ventilation is inappropriate, even if patients initially express a desire for life-prolonging measures. Usually, education and thoughtful discussions about patient and family goals are effective in guiding decisions toward appropriate care in these settings. If possible, discussion about the risks and benefits of ventilation, along with issues about CPR, should be undertaken before a crisis occurs that precipitates the need for a decision. Patients seriously considering prolonged mechanical ventilation need to understand clearly, in advance, the severe limitations, effects on quality of life, and frequent complications associated with permanent ventilator dependency.
Bilevel positive airway pressure (BiPAP) provides positive pressure to facilitate inspiration and maintains low levels of pressure in the circuit during expiration to reduce airway collapse. This may be a helpful option for patients with lung disease who need extra ventilatory support at night or during part of the day to avoid fatigue or maintain adequate blood gases. The difference between BiPAP and a ventilator needs to be discussed carefully to help patients decide which, if either, will help them achieve their goals. Careful thought needs to go into the process of selecting BiPAP as an option to support a terminal patient dying with pulmonary complications. BiPAP may help to postpone, but usually cannot prevent, ultimate respiratory failure. Patient goals and expectations should be carefully explored before deciding to use this treatment modality.
Discontinuation of Ventilators
Ventilator-dependent patients, or their designated decisionmakers, sometimes choose to stop ventilator support once it has been initiated. They may decide that the quality of life associated with ventilator dependency is not acceptable or they may no longer desire life-prolonging interventions. These are reasonable choices and are ethically acceptable to most people based on the premise that discontinuation of an intervention that artificially prolongs life is not different from choosing to forego the treatment in the first place.
It is essential to be certain that the decisionmakers and others who care about the patient understand clearly that the expected outcome of discontinuing ventilation is death. The possible processes leading to death, such as immediate cessation of breathing or a more prolonged period of gradual respiratory failure, should be explained, when appropriate.
Once decisions have been finalized, a specific time can be set for discontinuing ventilation. There are advantages to allowing all participants to have time to review the decision and "sleep on it" by scheduling the procedure for the next day or later. Support for family and friends by chaplains, social workers, or others can be planned in advance. The patient should be placed in an area that offers privacy and space for all family and friends who need to be present. It is important to allow, even encourage, rituals that have meaning for the patient and family, such as prayers, readings or singing. The specific details of such plans depend on the beliefs and culture of those who will be present.
Plans for the use of supplemental oxygen should be considered before terminating ventilator support. If oxygen supplementation will be stopped, it is often helpful to titrate concentrations down to room air before discontinuing the ventilator. If it will be continued, then the concentration should be reduced to levels easily supported by a simple mask (35% to 50%) or a nasal cannula (30% to 35%).
The process of discontinuation of mechanical ventilation is simple and usually uneventful. Patients can be prepared with intravenous access and sedated, if necessary, with intravenous midazolam or lorazepam. It is difficult to imagine any circumstances where paralytic agents would be appropriate during discontinuation of the ventilator. Once sedated, intravenous morphine (starting with 2 to 4 mg if opioid-naive) can be titrated to suppress the sensation of dyspnea, and tracheal suctioning may be done one final time.
The ventilator can then be disconnected at the endotracheal tube, replaced by a blow-by circuit, or switched to a ventilator mode with no positive pressure ventilation. Alarms should be silenced and unnecessary monitoring devices removed.
If an endotracheal (ET) tube is in place, there is often a desire to extubate the patient at the time of discontinuing the ventilator. Again, this decision should be carefully considered in advance. Extubation provides a more normal appearance for the patient, removes the resistance associated with breathing through a tube, and may allow the patient to talk. However, suctioning and airway protection will be more difficult without the tube in place.
Some patients occasionally have a reflex laryngospasm from the irritation of the ET tube when it is removed and are unable to breathe. While this symptom can be treated with rapid administration of additional intravenous midazolam or morphine, it may be alarming to friends and family. The development of agonal respiration and "death rattle" may also be distressing to observers and is more easily managed with suction available through the ET tube. The decisions are easier with a tracheostomy since the tracheostomy tube can be left in place without the drawbacks of an oral or nasal endotracheal tube.
Many patients continue to breathe on their own for hours to days after discontinuation of mechanical ventilation. The discussion, in advance, of the likely outcomes of ventilator discontinuation will prepare the family and friends for this possibility. A patient coming off the ventilator can be managed just like a person with respiratory failure who chooses not to be placed on a ventilator in the first place. Dyspnea can be treated with opioids and anxiety can be treated with lorazepam, as described in the section below, Symptom Management.
Whether patients live for minutes or days after removal of mechanical ventilation, their symptoms usually can be controlled effectively and their suffering prevented. When this is done carefully, the goals and desires of patients and their loved ones are honored through the process of ventilator discontinuation.
The Option of Continuous Sedation for Respiratory Distress
Sometimes, standard palliative measures fail to give effective relief from respiratory symptoms. This can occur when a patient's anxiety level is very high, when symptoms are frightening or associated with the sensation of being unable to breathe, or when the patient is fearful of death. In these situations, if all other measures have failed, symptomatic relief may be possible only with continuous sedation. This is obviously a serious decision and must have the full support of the patient (if possible), family, friends, and the entire care team. All involved must recognize that the patient will be unable to eat and is likely to die without awakening. In some settings a formal informed consent may be desirable.
Once the decision for continuous sedation has been made, several options are possible (Table 6-2, PDF). Patient symptoms can sometimes be treated with increasing doses of benzodiazepines (lorazepam 1 to 3 mg every 4 to 6 hours orally or intravenously) and opioids (morphine 2 to 5 mg parenterally or 5 to 15 mg orally, if opioid-naive). Doses can be titrated upward if needed to control symptoms or as the disease progresses.
If lorazepam is not sufficient to sedate a frightened, anxious patient who is struggling to breathe, midazolam can be used. A loading dose of midazolam can be administered intravenously, or if necessary, subcutaneously, at a rate not greater than 1 to 2 mg per minute until the desired level of sedation is achieved. Doses in the range of 3 to 15 mg are often needed; the actual dose should be titrated against symptoms to achieve peaceful sedation. Sedation can be maintained with a continuous infusion of midazolam given intravenously or subcutaneously (starting with between 1 and 3 mg an hour and titrating upward to 5 to 10 mg/hour, if needed).
Often, a longer-acting benzodiazepine such as diazepam (5 to 10 mg rectally or parenterally every 4 to 12 hours) is effective in maintaining sedation. Morphine can be added to help suppress the sensation of dyspnea, if needed.
Barbiturates can also be used to maintain sedation. Pentobarbital (100 to 200 mg IM, intravenously or rectally every 4 to 6 hours) and phenobarbital (60 to 120 mg rectally or IM every 6 to 12 hours) are both very effective in maintaining sedation and may help to reduce benzodiazepine doses. Medication doses may need to be adjusted frequently and these patients often require high levels to maintain comfort. However, with careful attention to the details of dosing, continuous sedation and a peaceful death are possible.
Options for Patient Control Over the End-of-Life Events
Before recommending life-prolonging interventions for a terminally ill patient, it is essential to have a clear idea of how a suggested treatment will enhance the person's quality of life or help him or her to meet specific goals. Just because we can intervene to prolong life, doesn't necessarily mean that we always should. More often than we may recognize, "letting nature take its course" results in the least suffering and the easiest process of dying possible under the circumstances. Patients need to know this.
It is obviously important for patients to understand their treatment options all through the course of their disease. As they approach the end of life, this is no less important. Patients need to know that they have more control over the final events of their lives than they sometimes realize. It is the role of patients, armed with accurate information about the status of their disease and prognosis, to decide when it is time to stop "fighting" the disease. This important transition allows patients to begin focusing their remaining energy toward completing the business of living and giving attention to the work of preparing to die. During this process, they can be offered the further options of choosing or refusing antibiotics or other life-prolonging medications, fluids, artificial nutrition, or blood transfusions. Patients also need to understand how exercising these options can affect the timing and manner of death. Sharing this information with people can be difficult and the timing is critical. However, for most patients, this information is ultimately reassuring and comforting.
Promises to Keep
Although respiratory symptoms have the potential to be frightening and distressing, applying the principles of palliative medicine allows most people to die comfortably and peacefully. It is often very reassuring to patients and those who love them to know in advance that suffering can be prevented and symptoms controlled with the use of appropriate medications. An old French adage suggested that the role of medicine was "to cure sometimes, to relieve often, to comfort always." With the knowledge and drugs available now, we can almost always relieve, as well as comfort. We can make promises to patients that weren't possible a few decades ago, promises of comfort and relief from suffering. Patients need to know this -- in advance. And then, when the time comes, they need to experience the reality of that reassurance.
Management of Pulmonary Secretions
Secretions associated with pulmonary infections or chronic bronchitis can produce troubling symptoms for patients, particularly as increasing weakness and fatigue make coughing exhausting and less effective. For patients who are still able to cough effectively, interventions should be directed at reducing the exertion required to bring up secretions. (See Table 6-3, PDF.) This involves the use of expectorants like guaifenesin which may increase sputum volume and decrease viscosity. To avoid patient fatigue, it may be appropriate to use preparations that combine dextromethorphan with an expectorant in order to raise the threshold for coughing while attempting to thin secretions.
The mucolytic drug, N-acetylcysteine, can reduce the internal disulfide cross-linking of tenacious secretions and may allow easier expectoration. This drug has been widely used in Europe as an oral medication without significant side effects, when administered in doses of 600 to 1200 mg twice a day. Although N-acetylcysteine is not approved by the FDA for oral use in the United States, it is often available at American health food and vitamin stores. The only preparation of N-acetylcysteine approved in the U.S. is a solution (Mucomyst or Mucosil) which can be aerosolized for inhalation (3 to 5 ml of 20% solution) up to four times a day or instilled directly through a tracheostomy (1 to 2 ml of 20% solution) every 1 to 4 hours. This preparation may be irritating to the airways and is not used frequently because of the risk of inducing bronchospasm.
Dehydration can increase sputum viscosity and exacerbate difficulties with expectoration. Systemic hydration, orally or intravenously, is the most effective solution to this problem. Humidification of inhaled oxygen is a helpful comfort measure to reduce symptoms of upper airway drying when oxygen is being administered. However, little effective hydration and thinning of pulmonary secretions occurs with airway humidification or use of saline aerosols.
Antihistamines can be useful in controlling a number of uncomfortable pulmonary symptoms associated with allergen-induced bronchospasm or rhinnitis. These drugs are used frequently in palliative medicine to treat nausea, vestibular disorders, anxiety and, occasionally, pulmonary secretions at the end of life. However, antihistamines have a marked drying effect on pulmonary secretions and can produce secretions that are thick, tenacious and difficult to expectorate. This can lead to mucus plugging of airways and result in worsening of ventilation-perfusion mismatching in the lungs. Some of the negative effects of antihistamines may be partially offset with diligent efforts to maintain good hydration, but the risks of the use of these drugs must always be weighed against the benefits, especially in patients with increased production of pulmonary secretions.
During the terminal stages of life, patients may be more comfortable if bothersome secretions in the trachea, larynx and pharynx are reduced. Even if patients are not alert enough to suffer distress caused by airway secretions, the airway sounds associated with dying ("death rattle") may be profoundly disturbing to family, friends, and caregivers. Since salivary and bronchial mucus glands are stimulated by cholinergic input, anticholinergic drugs may reduce upper airway secretions from these sources.
Scopolamine transdermal patches (1.5 mg, with 1 to 3 applied at a time, replaced every 3 days), hyoscyamine sulfate (0.125 to 0.25 mg oral or subcutaneous every 4 hours), or atropine (0.4 to 0.8 mg oral or subcutaneous) can be effective in reducing secretion production if given early enough. Antihistamines such as diphenhydramine (25 to 50 mg every 4 to 6 hours) are effective drying agents occasionally used in the final hours of life to control secretions. The "death rattle" may partially respond to frequent repositioning of the patient, with a special effort to avoid flat or supine positions that allow pooling of secretions in the pharynx or larynx.
Treatment of Dyspnea
Dyspnea is a general term that describes a subjective sensation, an "uncomfortable awareness of breathing."11 Patients may use a variety of words or phrases to explain these distressing symptoms, such as chest tightness, breathlessness, air hunger, unable to take a deep breath, feeling of suffocation or smothering, or unable to get enough air.12 The symptoms usually worsen with exertion and often limit the patient's activity. Extensive research has not yet provided a simple, clear explanation of the physiological basis for the symptom of dyspnea. One reasonable explanation is that the sensation of shortness of breath occurs when the air movement or "stretch" in the lungs is disproportional to the respiratory effort involved in breathing. This may be exacerbated when a patient's respiratory muscles are fatigued or have inadequate energy stores.
Surveys of outpatients with HIV/AIDS indicate that shortness of breath or dyspnea was identified as a problem by between 11% and 48% of the patients.13 The differential diagnosis of dyspnea in AIDS patients includes pulmonary infections, pulmonary malignancies, pleural effusions, congestive heart failure, marked anemia, and metabolic abnormalities. Malnutrition and weakness can lead to chronic respiratory muscle fatigue that also contributes to dyspnea. Anxiety and fear can precipitate or worsen this symptom in combination with other etiologies.
The sensation of dyspnea is not necessarily associated with low oxygen tension in the blood. In fact, the oxygen saturation of hemoglobin and oxygen partial pressure in blood are often normal in spite of very distressing symptoms. On the other hand, some patients with significant hypoxemia have little or no feeling of dyspnea associated with their abnormal blood gases. In addition, the severity of dyspnea does not necessarily correlate with the severity of pulmonary disease or pulmonary function test values. While dyspnea is usually associated with pulmonary or cardiac disease, it can occur with no detectable evidence of abnormalities in these organs. Even in terminally ill cancer patients, 24% had no evidence of pulmonary or cardiac disease to explain symptoms of dyspnea.14 For patients with some exercise tolerance, the etiology of dyspnea can be evaluated with a pulmonary exercise test that measures expired and arterial gases during strenuous exercise. However, this approach is seldom practical or useful in patients with terminal illnesses.
Treatment of Reversible Causes of Dyspnea
Palliative care aims to relieve the discomfort associated with feeling short of breath, regardless of the origin of the symptom. The first step in treatment is to identify any reversible causes of dyspnea and treat these with appropriate medications such as diuretics, bronchodilators, or steroids (Table 6-4). Corticosteroids, in particular, are used generously in palliative medicine, not only for relief of bronchospasm but also to reduce symptoms associated with swelling around tumor masses or inflammatory response to infections such as PCP. With pulmonary infection, particularly PCP, antibiotics may be beneficial in treating the underlying process, but discomfort usually can be well controlled with opioids and/or corticosteroids, even if the patient has decided to forego the use of further life-prolonging antibiotics.
Symptomatic Treatment of Dyspnea
Oxygen may be therapeutic if hypoxemia is stimulating increased respiratory effort and contributing to fatigue. As discussed earlier (see section, "Use of Oxygen in Terminal Care"), it is not clear how often this occurs. For normoxic patients, low flow oxygen (1 to 3 liters/minute) may provide a beneficial sensation of air flowing through the upper respiratory tract and may help reduce anxiety or fear associated with the feeling of being unable to get enough air. (See Table 6-5, PDF.)
For some dyspneic patients, cool temperatures and/or a fan blowing air in the face can also be helpful. Positioning is often critical for comfort and is usually determined by patient preferences. In some settings, people may find it helpful to lie on the side with the "good" lung down to reduce ventilation-perfusion mismatch. However, when fluid or secretions are present, keeping the good lung up may facilitate drainage away from the healthier gas exchange surfaces. In any case, frequent repositioning can help limit dependent lung consolidation.
Other nonpharmacologic measures that have been used to palliate symptoms of dyspnea include relaxation techniques, massage, acupuncture and guided imagery. Further studies of the effectiveness of each of these approaches would be helpful.
Although large pleural effusions are not common with PCP or other AIDS-related processes, thoracentesis may provide relief when patients have symptomatic effusions. Malignant effusions tend to re-accumulate rapidly, often within a few days, making repeated thoracenteses minimally beneficial. Thoracentesis also may contribute to protein depletion (two liters of malignant effusion may contain 80 grams of protein) and may increase loculation of fluid which makes future pleurodesis less likely to be successful. Pleurodesis, and even pleuroperitoneal shunts, can reduce dyspnea caused by large recurrent pleural effusions when the patient has an adequate life expectancy to justify the stress and discomfort associated with the procedure.
For dyspnea that persists in spite of specific therapy, opioids have been found to significantly reduce this distressing sensation in end-stage disease.15 In opioid-naive patients, 3 to 5 mg of oral morphine solution can be given every 3 to 4 hours and the dose titrated upward to 10 to 20 mg if needed. If symptoms persist, anxiolytic medications such as lorazepam should be added or increased before titrating opioids much higher. Sublingual administration of an oral morphine solution (usually 20 mg/ml) is often successful in patients who need very low doses, have limited swallowing capacity, or are not alert. For patients who do not tolerate oral administration of the drug, morphine tablets can be used rectally at oral doses, or injectable morphine can be given subcutaneously or intravenously using approximately one third of the oral dose (starting with 1 to 2 mg).
In recent years, there have been reports of the use of aerosolized morphine to treat dyspnea. At this point, there is no compelling evidence that this route of administration is superior to the use of oral or subcutaneous morphine. Although the mechanism by which opioids palliate dyspnea is not completely understood, it is likely (though not proven) that opioids work primarily at central receptors which mediate a decrease in the sensation of discomfort. Thus, there probably is not a strong basis for selecting nebulized opioids over oral or subcutaneous routes of administration unless the patient indicates a definite preference. If nebulized opioids will be used, the risk of histamine-induced bronchospasm should be considered. There may be an advantage to using fentanyl rather than morphine because fentanyl is thought to be less likely to stimulate histamine release, although bronchospasm with fentanyl has been reported.16
It is usually helpful to initiate treatment with benzodiazepines along with the morphine when treating dyspnea. Severe dyspnea almost always is associated with an understandable sense of anxiety, and at times, panic. These symptoms can be addressed with small doses of lorazepam (usually beginning with 0.5 mg) every 6 to 8 hours, given orally or sublingually. The dosing interval can be reduced to every 4 hours if needed and some patients require increasing the dose to 1 or 2 mg or sometimes more. The oral lorazepam tablets can be easily dissolved in a small amount of water, or even the morphine solution, if the patient has difficulty swallowing pills. A concentrated lorazepam solution (2 mg/ml) is also useful for these patients.
If symptoms occur less than once or twice a day, these medications can be offered as needed. If symptoms persist or occur regularly, discomfort is controlled best if the medications are given at regular intervals around the clock. For some patients, frequent, regular doses appear to be more effective than long-acting opioids, perhaps because of the recurrent reminder that the symptoms are being carefully treated. However, it is reasonable to attempt a trial of long-acting morphine (beginning with 15 mg every 12 hours) when the total daily dose of oral short acting morphine approaches 30 mg in 24 hours.
Treatment of Cough
Cough is a common symptom in AIDS, reported by 19% to 34% of patients in surveys of symptom prevalence in HIV disease.13 Coughing may result from pulmonary infection with secretion production, chronic bronchitis, bronchospasm, tumors in the airways, restrictive lung diseases, aspiration, post-nasal drip, drugs such as the angiotensin-converting enzyme inhibitors, unrecognized esophogeal reflux with aspiration, or inhaled irritants.
When cough is nonproductive, bronchospasm and reflux should be included in the differential diagnoses. A history of COPD, smoking, or asthma is helpful in making the diagnosis of bronchospasm, but it can occur with no relevant history. Physical signs include a prolonged expiratory phase of respiration, use of accessory muscles, decreased air movement, and wheezing which may be elicited only on forced expiration.
Cough from bronchspasm often responds to bronchodilators including albuterol (or salbutamol), salmeterol, ipratropium bromide, and either inhaled or systemic corticosteroids. In patients who are moving little air with each breath, systemic corticosteroids and frequent nebulization of bronchodilators may be needed. If symptoms improve and tidal volumes increase, hand-held metered dose inhalers may be effective. If esophogeal reflux is suspected, a trial of H2 receptor antagonists or proton pump inhibitors may be appropriate.
When cough suppression is needed to prevent exhaustion or control an irritating, nonproductive cough, several drug choices are available (Table 6-6, PDF). Dextromethorphan may raise the cough threshold, but in many cases opioids are needed to suppress the cough reflex. Antitussive doses of codeine start at 10 to 20 mg every 4 hours; upward titration is frequently needed and doses as high as 120 mg have been described, though not recommended.
For routine use, hydrocodone is preferred over codeine because it has fewer side effects and generally is tolerated better. Hydrocodone doses start at 5 mg every 4 to 6 hours and may be increased as needed. Morphine or other opioids can also be used for cough suppression, beginning with low doses (2 to 5 mg of oral morphine every 4 hours). If parenteral doses are necessary, approximately one third of the oral morphine dose can be given intravenously or subcutaneously at the same dose frequency. Doses can be increased, as necessary, by carefully titrating effectiveness in cough suppression against side effects.
For an irritating, nonproductive cough, nebulized lidocaine can sometimes provide rapid relief. 17, 18 Three ml of a 2% lidocaine solution (without epinephrine) can be nebulized three to four times a day as needed. Because of the risk of decreasing the sensitivity of the gag reflex with this anesthetic agent, patients should be advised to avoid eating or drinking after treatments for at least an hour, although sips of water are usually tolerated within minutes. There is some risk of inducing bronchospasm and so lidocaine should be used cautiously in patients with asthma.
Treatment of Noncardiac Chest Pain
Lung tissue is generally not well innervated with sensory nerves and therefore many invasive diseases that involve the alveoli and lower airways cause little pain. The pleural surfaces, on the other hand, are supplied with an extensive network of sensory nerves and often are exquisitely sensitive to inflammatory or invasive disorders. Pleural pain usually is sharp and aggravated by deep breathing or coughing. Airway inflammation can cause discomfort in the anterior retrosternal chest, and it is thought that pulmonary hypertension also can cause a nonspecific discomfort anteriorly over the hilar regions. Sharp or aching chest wall pain can be caused by bone metastases, rib fractures, or muscle injuries (occasionally from coughing).
Most pain in the lungs and chest wall responds well to usual pain medications. Anti-inflammatory drugs alone, such as aspirin, trilisate, acetaminophen, ibuprofen or naproxen, may be effective. If stronger drugs are needed, combination opioid/acetaminophen preparations such as hydrocodone (2.5 to 10 mg hydrocodone/500 mg acetaminophen) every 4 hours or oxycodone (5 mg oxycodone/325 to 500 mg acetaminophen) may be effective, but total daily doses of acetaminophen should be monitored to avoid exceeding 4 g/day. If higher doses of opioids are needed, routine doses of morphine or oxycodone can be started and titrated upward as needed while continuing standard doses of anti-inflammatory drugs around the clock.
Treatment of Hiccup
Persistent hiccup is not unusual in terminally ill AIDS patients and can be a distracting and distressing symptom.19 Because of the interruption of normal activity, patients with intractable hiccup can have depression, sleep deprivation, decreased oral intake, and weight loss. Suspected causes of hiccups include phrenic nerve or diaphragmatic irritation by tumor, gastric distension, gastroesphogeal reflux, and severe esophogeal candidiasis. Drugs such as benzodiazepines, corticosteroids and barbiturates have been reported to precipitate hiccup.19
If simple mechanical measures such as drinking from the "wrong side" of the glass and swallowing "up hill" against gravity,13 hypoventilation or carbon dioxide accumulation by breath-holding or breathing into an enclosed space, cold oral fluids or other vagal stimulations do not reduce the symptoms, medications can be used (Table 6-7, PDF). Chlorpromazine (12.5 to 50 mg) is sometimes helpful and can be given routinely for prophylaxis if necessary. If gastric distension is likely, metochlopramide (5 to 20 mg orally, rectally or intravenously three to four times a day) may help, and as a last resort, a nasogastric tube, inserted transiently to decompress the stomach, may provide relief.
Other treatments with reported benefits include baclofen (10 to 20 mg tid), valproic acid, and haloperidol.19 For intractable hiccup, intravenous or subcutaneous midazolam has been reported to be effective as a bolus (5 to 10 mg), followed, if necessary, by a maintenance continuous infusion (1 to 5 mg/hr).20
Management of Hemoptysis
Coughing up blood or bloody sputum can be a frightening experience, but usually is not life-threatening. It may at times be difficult to determine whether or not the source of bleeding is in the lungs. Nasal, pharyngeal, and upper esophogeal blood may also ooze into the upper airways and be coughed up.
The most common pulmonary causes of hemoptysis are infections, such as bronchitis or tuberculosis, and neoplasms. In the majority of cases, blood in the sputum can be managed by treating the underlying infection or suppressing cough to reduce the irritation and shear forces within the airways caused by vigorous coughing. An expectorant, and control of bronchspasm if present, may also be helpful. Coughing can usually be suppressed with opioids as described above, starting with hydrocodone-containing cough preparations and moving to 3 to 5 mg of oral morphine every 3 to 4 hours, if needed. The dose can be titrated upward when appropriate. If parenteral doses are necessary, approximately one third of the oral dose of morphine can be given intravenously or subcutaneously.
If bleeding is associated with low platelets or a coagulopathy, it may be possible to reduce bleeding in the lungs by treating the hematological abnormalities. On the other hand, there may be times at the end of life when the underlying disorders are not reversed easily or when treatment would only serve to prolong the dying process. In these situations, the most important therapy may be to suppress cough and prepare the patient and family for the results of persistent bleeding. Bronchial artery embolization or bronchoscopic interventions are possible for severe hemoptysis, but these approaches probably have limited value in terminally ill patients.
Malignancies and severe infections rarely erode from air spaces into large vessels, but the result can be devastating when this occurs. Massive bleeding can impair respiratory function, obstruct airways, and exsanguinate the patient. In most terminally ill patients, a focus on the relief of suffering is the most appropriate response. Symptoms of air hunger and choking may require rapid and complete sedation with benzodiazepines and/or opioids. Midazolam can be given intravenously or subcutaneously beginning with 2 to 4 mg and titrating quickly upward to 10 to 15 mg if the patient is still awake and struggling. Larger doses of midazolam may be needed if there appears to be airway obstruction by blood clots and impending asphyxiation. In these settings, it may be helpful to add parenteral morphine (5 to 10 mg) intravenously or subcutaneously.
In situations where injectable drugs are not available, large doses of morphine solution (20 to 40 mg) and lorazepam (2 to 4 mg given sublingually) or diazepam (10 mg orally or rectally) may be appropriate. In patients where significant hemorrhage is a strong possibility, it is helpful to keep dark towels at the bedside to help lessen the visual trauma to patient and family members associated with large amounts of bright red blood.
Treatment of Airway Obstruction
Patients who have airway obstruction from endobronchial masses or extrinsic compression often experience worsening dyspnea and increasing anxiety. These symptoms may be accompanied by signs of stridor, decreased intrathoracic air movement, wheezing, or cyanosis.
Corticosteroids may be helpful in reducing swelling and inflammation at any time in the progression of the disease. If the disease is identified early enough, interventions including external radiation therapy, bronchoscopic laser treatment, airway stent placement, or internal radioisotope application may provide at least temporary symptomatic relief.
When airway compromise is advanced, there may be no effective therapeutic options available. The focus of treatment then needs to be directed toward control of symptoms of fear, anxiety and dyspnea. These symptoms can be addressed with increasing doses of benzodiazepines such as lorazepam (beginning with 1 to 3 mg every 4 to 6 hours) and opioids (morphine, 2 to 5 mg parenterally or 5 to 15 mg orally every 2 to 4 hours). Doses can be titrated upward as needed.
As airway obstruction progresses, symptoms of severe respiratory distress and/or panic can be anticipated. At this point it may be necessary to use continuous sedation to prevent suffering. It is essential to discuss this option carefully in advance with the patient and family, since the patient is likely to die without awakening. If lorazepam is not sufficient to sedate a frightened, anxious patient who is struggling to breathe, midazolam can be carefully titrated to sedation with a loading dose of 3 to 15 mg intravenously or subcutaneously, usually given at a rate not greater than 1 to 2 mg per minute. Sedation can be maintained with a continuous infusion of midazolam given intravenously or subcutaneously, or routine doses of longer-acting benzodiazepines. Morphine can be added, intermittently or continuously via PCA, to help suppress the sensation of severe dyspnea. Addition of barbiturates often helps to maintain sedation and reduce required doses of benzodiazepines. Pentobarbital, 100 to 200 mg, can be administered orally, rectally or parenterally every 3 to 4 hours as needed. Phenobarbital doses of 60 to 120 mg can be given by similar routes every 6 to 12 hours. Doses of drugs need to be adjusted frequently and the patient may require extraordinarily high doses of medications (5 to 15 mg/hour of midazolam) to maintain comfort as the airway obstruction progresses. However, with careful attention to the details of dosing, continuous sedation and a peaceful death are possible.
Palliative Treatment of Respiratory Depression
When serious respiratory depression occurs from excess opiods, patients respond well to careful titration of naloxone. One ampule of 0.4 mg of naloxone can be diluted in 9 ml of saline and then one ml (0.04 mg) of this solution can be injected every five minutes until specific symptoms such as respiratory depression or hypotension are reversed. The goal is to treat the symptoms and not to totally reverse the opioid effect. The doses required to treat life-threatening symptoms usually are not disturbing to the recipient and often do not even awaken the patient.
Caring for people who are terminally ill is a unique, but rewarding, challenge for health care providers. As patients face progressive, incurable diseases, we are now able to reassure them that even their most distressing physical symptoms can be relieved. The less obvious sources of distress, such as loss of independence, anxiety about being a burden to family, unfulfilled dreams, the impending separation from loved ones, unresolved conflicts or guilt, and the need to redefine the goals and purpose of life, also require attention. In addition to effective symptom management, out patients need a safe environment, willing listeners, and a sense of being valued. They also need accurate information about their disease, an understanding of treatment options, ideas of what to expect in the future, and as much control of their lives as possible. When these needs are met, the majority of terminally ill people experience a peaceful and comfortable death.
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