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An approach to dyspnea in cancer patients
76
Journal
of
Pain and Symptom Management
Vol. 4 No. 2June
Special Article
10x4
“‘Issuesin Symptom Control” Part 5
An Approach to Dyspnea in Cancer Patients David Fishbein, MD, Clive Kearon, MD and Kieran J. Killian, MD of Medicine, McMaster University, Hamilton, Ontario, Canada
Department
Abstract There are many potential causes of dyspnea in the patient with cancer. Ultimately, a sense of increased respiratory effort Zscommon to all of these diverse situations. An organized approach to dysjmea in the cancer patient is presented based on psychophysical pinciples, and treatment modalities are suggested. J Pain Symptom Manage 1989;4:76-81 Key Words Psychophysics,respiratory effort, metabolic demands, central drive, venous admixture, respiratory muscles, impedance, resistance, elastance, palliation
Introductiirm As the lungs are among the organs most commonly involved in primary and metastatic cancer, the management of dyspnea in patients with advanced cancer is a significant problem. Lung cancer is the leading cause of death due to malignancy in men aged 35 years or older, and has recently eclipsed breast cancer as the leading fatal malignancy among similarly aged women in Canada and the United States. In the United States in 1983, the incidence of lung cancer was approximately 94,000 males and 41,000 females, causing 35% of all male, and 17% of all female cancer deaths.’ Furthermore, the lungs are the second most common site of metastases in patients dying of malignancy, with 29% of patients having pulmonary metastatic disease at autopsy. 2 Since dyspnea is such a frequent and distressing symptom in these pa-
tients, its effective treatment and palliation should be a priority for all physicians. The pathophysiologic mechanisms accounting for breathlessness in patients with advanced cancer are numerous and varied, and an understanding of these factors is required to rationalize management in this population.
SensoryMechaksms of Breaddesswss Until recently, investigators have focused on a neuroanatomical approach to identify the receptor, mode of transmission, and neural pathways responsible for breathlessness. Putative sources of breathlessness, acting individually or in combination, have included chemoreceptors, the medullary respiratory complex, intrapulmonary receptors, sensory receptors within the respiratory muscles, and efferent activity in the motor pathway. s Intrapulmonary J-receptors, which are located close to the alveoli and pulmonary
Address reprint requests to: Kieran J. Killian, MD, Ambrose Cardiorespiratory Unit, McMaster University Medical Center, 1200 Main Street West, Hamilton, Ontario L8N 325, Canada. Accepted for publication: August 4, 1988
1989 York
have
also been
implicated.
or mecha-
nisms, dyspnea is perceived by the patient as discomfort associated with the act of breathing. Like any conscious sensation, it can be quanti-
The editors of this special series on symptom control are Eduardo 0 U.S. Cancer Pain Relief Committee, Published by Elsevier, New York, New
capillaries,
Regardless of the neuroanatomy
Bruera,
MD and R. Neil MacDonald,
MD.
Vol. 4 No. 2 June 1989
Dyjmea
77
in Cancer Patient5
fied, and the relationship between the physical stimuli giving rise to dyspnea and the sensation itself can be studied. This field of study, termed psychophysics, has considerably advanced our understanding of the pathophysiology of dyspnea.* Application of psychophysical principles has demonstrated that dyspnea is ultimately dependent on proprioceptive information generated during the act of breathing, and that respiratory effort is the specific sensation most closely related to dyspnea. This is consistent with both a large body of accumulated experimental evidence, as well as circumstantial evidence. In terms of the latter, the various clinical situations in which dyspnea occurs share the common denominator of increased respiratory effort. Respiratory effort is increased when the demand for ventilation is increased (e.g., exercise), the impedance of the respiratory system is increased (e.g., restrictive and obstructive ventilatory defects), the inspiratory muscles are weakened by either fatigue or disease (e.g., myopathies, neuropathies), the intrinsic characteristics of the muscles are at a mechanical disadvantage (e.g., adverse length-to-tension or force-to-velocity relationships), the muscle is working at a mechanical disadvantage (e.g., distortion of the chest cage, such as in kyphoscoliosis), or any combination of these factors. Breathlessness may not be entirely generated by an awareness of the outgoing motor command, because the quality of sensation is also dependent on feedback from the respiratory muscles, conveying information about tension, displacement, impedance and sometimes even pain.5 The relationship between dyspnea and the sense of respiratory effort serves as a useful framework when approaching cancer patients with dyspnea.
due to its elastance and resistance. To complete the cycle, ventilation is required to meet the patient’s metabolic demands, which quantitatively approximate the carbon dioxide production (Figure 1). Derangements anywhere along this pathway can lead to an enhanced central motor output, resulting in an increased sense of respiratory effort dyspnea. These problems are particularly frequent in patients with advanced cancer. The general therapeutic principles used to alleviate dyspnea in cardiopulmonary diseases are also applicable to patients with widespread cancer.
Intrinsic Metabolic De-mud The first determinant of central motor output and respiratory effort relates to metabolic demands. Activity leads to increased carbon dioxide production and ventilatory demands thereby contributing to breathlessness.6 In addition, conditions often coexist with cancer such as fever (due to sepsis or the tumor itself), anemia (due to marrow infiltration or suppression by chemotherapy, or nutritional factors), and acidosis (due to starvation ketoacidosis, or type B lactic acidosis because of extensive hepatic metastatic disease), which may contribute to increased dyspnea by increasing metabolic demands. Dyspnea can be lessened by correction of these factors with antipyretics, treatment of sepsis, and red cell transfusions, and by ensuring adequate nutritional intake.
Physidogical Contm’butim to Breathlessness Respiratory control centers initiate motor output to the respiratory muscles. This motor output results in the development of tension within the muscles, and eventually an effective driving pressure, which brings about ventilation. The relationship between the motor command and ventilation depends on neuromuscular excitation and the respiratory muscles, as well as the impedance of the respiratory system,
I
I
Fig 1. The intensity of dyspnea is closely related to respiratory muscle effort; respiratory effort is quantitatively related to the motor command acting on the inspiratory muscles. Many unit processes alone and in combination interact in quantifying the intensity of motor command-effort-dyspnea. See text for discussion of individual factors.
78
Pishbein et al.
Central Drive Although infrequently described, cerebral metastatic deposits impinging on the respiratory center and causing an enhanced central motor output are a potential cause of dyspnea. Generally, treatment is unsatisfactory but includes conventional modes of cancer therapy such as radiotherapy and chemotherapy.
Em
of GasExchange
Disturbances in the efficiency of carbon dioxide elimination and oxygen uptake frequently contribute to breathlessness by increasing ventilatory requirements. Conditions characterized by a high dead space (high V/Q) result in increased ventilation to achieve carbon dioxide elimination. Conversely, disorders leading to increased venous admixture (low V/Q) cause hypoxia, which further stimulates ventilation. The prototypic disorder that causes a high dead space to tidal volume ratio is pulmonary thromboembolism, which is treated with anticoagulation. While this is a well-described complication of malignancy, other pulmonary vascular diseases (such as tumor emboli, pulmonary hypertension) and parenchymal lung disorders also disturb V/Q relationships and reduce the efficiency of gas exchange. Under these circumstances, dyspnea may be ameliorated by the administration of supplemental oxygen to relieve hypoxia. The mode of administering the oxygen (either by nasal prongs or mask) is of secondary importance, as long as arterial oxygen saturation, monitored by arterial blood gases, or more simply by oximetry, is raised to greater than 90%. Although the relief of hypoxia is a rational indication for using oxygen, dyspneic patients with end-stage lung cancer are very often given oxygen without consideration of their arterial oxygen level, essentially as a form of palliation. In these situations, oxygen is likely to be of limited benefit.
Respiratory Muscles The degree of central motor output (and hence dyspnea) required to achieve adequate ventilation depends on both respiratory muscle strength and the impedance of the respiratory system. Respiratory muscle weakness and fatigue,
Journal of Pain and Symptom Management
due to several possible mechanisms, commonly contributes to breathlessness in patients with widespread cancer. Paraneoplastic syndromes are particularly frequent in primary lung cancer, and about 1% of patients manifest symptoms secondary to a neuropathic or myopathic syndrome at some point in their disease course. These include the Eaton-Lambert syndrome (predominantly due to small cell carcinoma), peripheral neuropathies, and dermatoand polymyositis. All of these conditions may involve the respiratory muscles, producing physiologically demonstrable respiratory muscle weakness, and often, clinically relevant dyspnea. Specific treatment directed at the respiratory muscles is usually not possible, but resolution of the paraneoplastic syndromes with treatment of the primary tumor has been documented. Respiratory muscle weakness may also be associated with the syndrome of anorexia and cachexia that is present in up to one third of lung cancer patients. Its etiology is unclear, but metabolic studies in noncachectic nonsmall cell lung cancer patients have demonstrated increased muscle catabolism.g A number of metabolic abnormalities may coexist in these patients, which can cause or aggravate preexisting weakness, including hypophosphatemia, hypocalcemia, and hypomagnesemia. This provides ample rationale for excluding and treating nutritional deficiencies in cancer patients, as they may worsen respiratory muscle weakness. Respiratory muscle weakness may also result from paralysis of a hemidiaphragm due to phrenic nerve involvement from intrathoracic spread of tumor. All of these problems coexist on a background of accelerating atrophy from disuse, which is secondary to reduced activation because of reduced activity. Assessment of respiratory muscle strength requires measurement of static maximum inspiratory and expiratory pressures. These simple maneuvers should be used to evaluate and follow patients with dyspnea and respiratory muscle weakness. Although there is a great deal of variability in these measurements among the general population, severe dyspnea is unlikely to ensue until they fall below 40 cm HsO. The demonstration of respiratory muscle weakness should prompt investigation to rule out neuropathic or myopathic paraneoplastic syndromes, cachexia, metabolic deficiencies, and diaphragmatic paralysis.
Vol. 4 No. 2 June I989
79
Dys@ea in Cancer Patients
Mechanical Efickncy of Respiratolr Muscles The ability of the respiratory muscles to generate pressure is reduced by inappropriate length-to-tension or force-to-velocity relationships. Breathlessness increases in situations where the inspiratory muscles are weakened by shortening their resting length, such as hyperinflation. lo Improvement in the operating characteristics of the muscle may occur with treatment of any reversible component (for example following bronchodilator therapy of the lung disease present), but this is often not feasible.
Impedance of the Respirahny System The majority of cancer patients are dyspneic because of increased impedance of the respiratory system due to increased airflow resistance, lung elastance, or a combination of both.
diation, surgical decompression, yag laser) or by systemic chemotherapy. Patients with localized airway obstruction, as well as generalized muscle weakness, often have difficulty clearing their secretions. Physiotherapy and aspiration of secretions may afford some symptomatic relief in these situations. Pleural effusions are a comEffusion. mon occurrence in intrathoracic malignancy, particularly with carcinomas of the lung and breast, or with lymphomas. Detection of a large pleural effusion should be followed by a therapeutic thoracentesis if the patient is dyspneic. Although a small number of patients will remain fluid-free after initial thoracentesis, in most the effusion recurs and consideration should be given to pleurodesis if a reasonable life span is anticipated and thoracentesis was effective in reducing breathlessness.‘*
Pleural
Both postobstructive pneumonia and pneumonia in areas remote from the sites of tumor cause breathlessness by increasing metabolic demands (pyrexia), altering gas exchange, and increasing pulmonary elastance. Diagnosis can usually be made from clinical presentation, chest radiograph, and sputum analysis. Breathlessness caused by pneumonia usually responds to appropriate antibiotics.
Znfection.
As the vast majority of primary lung cancers occur in smokers and roughly one fifth of smokers develop significant chronic airflow limitation, it is not surprising that many patients with lung cancer have symptomatic airflow limitation. This can be identified by simple spirometry (FEVJVC < 70%), or a flow volume loop. Treatment includes B2 adrenoreceptor agonists, theophylline derivatives, and inhaled or systemic corticosteroids,g which attempt to reverse diffuse airway obstruction. There is little rationale for withholding systemic corticosteroids in these patients because of concern over possible long-term sequelae. Steroids are often efficacious, affording considerable symptomatic relief in patients; in view of the expected short survival time, they should be used liberally. Localized airflow limitation due to upper airway obstruction (bilateral vocal cord paralysis; tumors of the pharynx, larynx, and thyroid), extrinsic compression (enlarged paratracheal or mediastinal nodes), or endobronchial tumor deposits are also common. Sites of localized obstruction may be suspected from the flow-tovolume curve which demonstrates cutoff of the inspiratory limb in variable extrathoracic obstruction, cutoff of the expiratory limb in variable intrathoracic obstruction, and a squaredoff appearance in fixed upper airway obstruction.” Reversal of localized obstruction may be achieved by specific local therapy (irra-
Aivjlow
Limitation.
Radiation
and
Drug-Znduced
Lung Disease.
Many of the therapeutic modalities used to treat malignancy may themselves cause lung damage and increase elastance. Radiation pneumonitis is diagnosed by a compatible clinical and radiographic presentation, and may respond to corticosteroids in the subacute phase, but is unlikely to do so in the chronic phase.13 Bleomycin, cyclophosphamide, methotrexate, and busulfan are among the many chemotherapeutic agents that can lead to pulmonary toxicity, causing primarily interstitial pneumonitis pathologically. They generally fail to respond to therapy, but a trial of corticosteroids is warranted, particularly if dyspnea is pronounced.14 Although these patients generally present with hypoxemia and radiographic infiltrates, frequently their presentation may be more subtle. The cancer patient with dyspnea and an apparently normal chest x-ray and arterial blood gases should still be thoroughly evaluated with pulmonary function testing, assessment of inspiratory muscle strength, gallium scanning,
80
Fishbein et al.
and, if indicated, an assessment of arterial oxygen saturation during exercise. Chest radiographs often are insensitive indicators of pulmonary involvement, and lag behind symptoms and pulmonary function tests, particularly the diffusing capacity. l5 The uptake of gallium by the lung is a nonspecific finding seen in several inflammatory diseases, but it may be an important clue to drug-induced lung disease.16 Similarly, arterial oxygen desaturation with exercise may reveal unsuspected gas exchange abnormalities. Lej Ventriculur Failure. Left ventricular failure, due to coexistent heart disease or as a complication of therapy, is also a relatively frequent event in patients with advanced cancer, and is treated in the same manner as in other patients, with diuretics, digoxin, and afterload reduction, depending on its severity. Lymphangitic Carcinomatosis. Among the most distressed and breathless of patients with widespread cancer are those with lymphangitic carcinomatosis, which can be suspected by its radiographic presentation (interstitial infiltrates associated with Kerley B lines) and confirmed, if necessary, by transbronchial biopsy. Although occasional improvements with systemic corticosteroids can be seen, these tend to be brief, and patients usually succumb within a short period of time, often with severe, unrelenting dyspnea. Progressive Intrathoracic Malignancy. Massive intraparenchymal tumors, primary or secondary, disorganize the lung, which decreases the efficiency of gas exchange and increases the impedance of the lung, resulting in central respiratory motor output sufficiently raised to produce dyspnea. Ultimately, treatment in this instance must be directed at the tumor itself, either with surgery, radiotherapy, or chemotherapy.
General Therapeutic P&ci.h Recognition of the factor or factors alone or in combination contributing to dyspnea is central to its successful management. As outlined in Figure 1, the various contributing factors all act in the final analysis by increasing central motor output. At each step in the paradigm, different processes impact, requiring different
Journal
oj Pain and Symptom Management
diagnostic and treatment strategies. This diagram will enable a systematic and organized approach to the investigation and treatment of the numerous causes of dyspnea in patients with advanced cancer. In some instances, therapy will have a clear beneficial effect on symptoms of breathlessness. However, all too often after completion of this evaluation and treatment of remediable conditions, one is left with a patient with advanced cancer with severe dyspnea, whose breathlessness is attributable to causes unresponsive to available specific treatment. The prospects for such patients are bleak and frequently their dyspnea persists unabated until their demise. In such a patient, treatment must leave the realm of therapy directed at a specific disease entity, and focus on pharmacotherapy intended to ameliorate the perception of breathlessness, rather than its cause. Studies to date have yielded conflicting results about the efficacy of various sedative narcotics in improving dyspnea. Most of these studies used benzodiazepines in modest doses.‘7-20 Such therapeutic conservatism is unwarranted in patients with advanced cancer and severe dyspnea, and in this situation opiates are a more appropriate choice. In addition to their anxiolytic effects, opiates decrease respiratory drive and lead to hypoventilation, and hence are efficacious in alleviating dyspnea. Morphine in judicious doses should therefore be used in patients with widespread cancer and intractable dyspnea not amenable to more specific therapy, to blunt the outgoing central motor command. In summary, we have presented a physiological approach to the management of dyspnea, which can be used as a framework for the categorization, evaluation and therapy of the numerous different conditions leading to breathlessness in patients with advanced cancer. This will allow the physician to determine if any condition amenable to therapy is responsible for the dyspnea and to proceed with appropriate therapy. Ultimately it should facilitate improved palliation of the severe, intractable dyspnea from which these patients often suffer.
References 1. Minna JD, Higgins GA, Glatstein EJ. Cancer of the lung. In: DeVita VT, Hillman S, Rosenberg SA, eds. Cancer-principles and practice of oncology, 2nd ed. Philadelphia: J.B. Lippincott, 1985:50’7-597.
Vol. 4 No. 2 June 1989
2. Willis RA. Pathology of tumors. ton-century Crofts, 1967:175.
Dysjmea in Cancer Patients
London:
3. Anonymous. The enigma of breathlessness. cet 1986;1:891-892. 4. Cherinack NS, Altose MD. Mechanisms pnea. Clin Chest Med 1987;8:207-214.
AppleLanof dys-
5. Killian KJ, Campbell EJM. Dyspnea. In: Roussos C, Macklem PT, eds. The thorax. New York: Marcel Decker, 1985:787-828. 6. Killian KJ, Campbell EJM. Dyspnea and exercise. Ann Rev Physiol 1983;45:465-479. 7. Tyler HR. Paraneoplastic syndromes of nerve, muscle and neuromuscular junction. Ann NY Acad Sci 1974;230:348-357. 8. Wilcox PC, Morrison NJ, Anzarut ARA, Pardy RL. Lambert-Eaton myasthenic syndrome involving the diaphragm. Chest 1988;93:604-606.
81
12. Haushera FH, Yarbro JW. Diagnosis and treatment of malignant pleural effusion. Semin Oncol 1985;12:54-75. 13. Gross NJ. Pulmonary effects of radiation Ann Intern Med 1977;86:81-92.
therapy.
14. Cooper JAD, White DA, Matthay RA. Drug-induced pulmonary disease. Am Rev Respir Dis 1986;133:321-340. 15. Ginsberg SJ, Comis RL. The pulmonary toxicity of antineoplastic agents. Semin Oncol 1982;9:34-51. 16. Richman SD, Levinson SM, Bunn PA, et al. Gallium-67 accumulation in pulmonary lesions associated with eleomycin toxicity. Cancer 1975;36: 19661972. 17. Mitchell-Heggs P, Murphy K, Minty K, et al. Diazepam in the treatment of the “pink-puffer” syndrome. Q J Med 1980;49:9-20.
9. Hever D, Chelbowski RT, Ishibashi DE, Harrold JN, Block JB. Abnormalities in glucose and protein catabolism in noncachectic lung cancer patients. Cancer Res 1982;42:48 15-4819.
18. Woodcock AS, Gross ER, Gellent A, et al. Effect of dihydrocodeine, alcohol and caffeine in breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med 1981;305:1611-1616.
10. Killian KJ, Gandevia SC, Summers E, Campbell EJM. Effect of increased lung volume on perception of breathlessness, effort and tension. J Appl Physiol 1984;57:6866-6891.
19. Woodcock AA, Groos ER, Geddes DM. Drug treatment in breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Br Med J 1981;283:343-346.
11. Kryger M, Bode F, Antic R, Anthonisen N. Diagnosis of obstruction of the upper and central airways. Am J Med 1976;61:85-93.
20. Man CGW, Hsu K, Sproule BJ. Effects of alprazolam on exercise and dyspnea in patients with chronic obstructive disease. Chest 1986;90:832-836.
Journal
of
Pain and Symptom Management
Vol. 4 No. 2June
Special Article
10x4
“‘Issuesin Symptom Control” Part 5
An Approach to Dyspnea in Cancer Patients David Fishbein, MD, Clive Kearon, MD and Kieran J. Killian, MD of Medicine, McMaster University, Hamilton, Ontario, Canada
Department
Abstract There are many potential causes of dyspnea in the patient with cancer. Ultimately, a sense of increased respiratory effort Zscommon to all of these diverse situations. An organized approach to dysjmea in the cancer patient is presented based on psychophysical pinciples, and treatment modalities are suggested. J Pain Symptom Manage 1989;4:76-81 Key Words Psychophysics,respiratory effort, metabolic demands, central drive, venous admixture, respiratory muscles, impedance, resistance, elastance, palliation
Introductiirm As the lungs are among the organs most commonly involved in primary and metastatic cancer, the management of dyspnea in patients with advanced cancer is a significant problem. Lung cancer is the leading cause of death due to malignancy in men aged 35 years or older, and has recently eclipsed breast cancer as the leading fatal malignancy among similarly aged women in Canada and the United States. In the United States in 1983, the incidence of lung cancer was approximately 94,000 males and 41,000 females, causing 35% of all male, and 17% of all female cancer deaths.’ Furthermore, the lungs are the second most common site of metastases in patients dying of malignancy, with 29% of patients having pulmonary metastatic disease at autopsy. 2 Since dyspnea is such a frequent and distressing symptom in these pa-
tients, its effective treatment and palliation should be a priority for all physicians. The pathophysiologic mechanisms accounting for breathlessness in patients with advanced cancer are numerous and varied, and an understanding of these factors is required to rationalize management in this population.
SensoryMechaksms of Breaddesswss Until recently, investigators have focused on a neuroanatomical approach to identify the receptor, mode of transmission, and neural pathways responsible for breathlessness. Putative sources of breathlessness, acting individually or in combination, have included chemoreceptors, the medullary respiratory complex, intrapulmonary receptors, sensory receptors within the respiratory muscles, and efferent activity in the motor pathway. s Intrapulmonary J-receptors, which are located close to the alveoli and pulmonary
Address reprint requests to: Kieran J. Killian, MD, Ambrose Cardiorespiratory Unit, McMaster University Medical Center, 1200 Main Street West, Hamilton, Ontario L8N 325, Canada. Accepted for publication: August 4, 1988
1989 York
have
also been
implicated.
or mecha-
nisms, dyspnea is perceived by the patient as discomfort associated with the act of breathing. Like any conscious sensation, it can be quanti-
The editors of this special series on symptom control are Eduardo 0 U.S. Cancer Pain Relief Committee, Published by Elsevier, New York, New
capillaries,
Regardless of the neuroanatomy
Bruera,
MD and R. Neil MacDonald,
MD.
Vol. 4 No. 2 June 1989
Dyjmea
77
in Cancer Patient5
fied, and the relationship between the physical stimuli giving rise to dyspnea and the sensation itself can be studied. This field of study, termed psychophysics, has considerably advanced our understanding of the pathophysiology of dyspnea.* Application of psychophysical principles has demonstrated that dyspnea is ultimately dependent on proprioceptive information generated during the act of breathing, and that respiratory effort is the specific sensation most closely related to dyspnea. This is consistent with both a large body of accumulated experimental evidence, as well as circumstantial evidence. In terms of the latter, the various clinical situations in which dyspnea occurs share the common denominator of increased respiratory effort. Respiratory effort is increased when the demand for ventilation is increased (e.g., exercise), the impedance of the respiratory system is increased (e.g., restrictive and obstructive ventilatory defects), the inspiratory muscles are weakened by either fatigue or disease (e.g., myopathies, neuropathies), the intrinsic characteristics of the muscles are at a mechanical disadvantage (e.g., adverse length-to-tension or force-to-velocity relationships), the muscle is working at a mechanical disadvantage (e.g., distortion of the chest cage, such as in kyphoscoliosis), or any combination of these factors. Breathlessness may not be entirely generated by an awareness of the outgoing motor command, because the quality of sensation is also dependent on feedback from the respiratory muscles, conveying information about tension, displacement, impedance and sometimes even pain.5 The relationship between dyspnea and the sense of respiratory effort serves as a useful framework when approaching cancer patients with dyspnea.
due to its elastance and resistance. To complete the cycle, ventilation is required to meet the patient’s metabolic demands, which quantitatively approximate the carbon dioxide production (Figure 1). Derangements anywhere along this pathway can lead to an enhanced central motor output, resulting in an increased sense of respiratory effort dyspnea. These problems are particularly frequent in patients with advanced cancer. The general therapeutic principles used to alleviate dyspnea in cardiopulmonary diseases are also applicable to patients with widespread cancer.
Intrinsic Metabolic De-mud The first determinant of central motor output and respiratory effort relates to metabolic demands. Activity leads to increased carbon dioxide production and ventilatory demands thereby contributing to breathlessness.6 In addition, conditions often coexist with cancer such as fever (due to sepsis or the tumor itself), anemia (due to marrow infiltration or suppression by chemotherapy, or nutritional factors), and acidosis (due to starvation ketoacidosis, or type B lactic acidosis because of extensive hepatic metastatic disease), which may contribute to increased dyspnea by increasing metabolic demands. Dyspnea can be lessened by correction of these factors with antipyretics, treatment of sepsis, and red cell transfusions, and by ensuring adequate nutritional intake.
Physidogical Contm’butim to Breathlessness Respiratory control centers initiate motor output to the respiratory muscles. This motor output results in the development of tension within the muscles, and eventually an effective driving pressure, which brings about ventilation. The relationship between the motor command and ventilation depends on neuromuscular excitation and the respiratory muscles, as well as the impedance of the respiratory system,
I
I
Fig 1. The intensity of dyspnea is closely related to respiratory muscle effort; respiratory effort is quantitatively related to the motor command acting on the inspiratory muscles. Many unit processes alone and in combination interact in quantifying the intensity of motor command-effort-dyspnea. See text for discussion of individual factors.
78
Pishbein et al.
Central Drive Although infrequently described, cerebral metastatic deposits impinging on the respiratory center and causing an enhanced central motor output are a potential cause of dyspnea. Generally, treatment is unsatisfactory but includes conventional modes of cancer therapy such as radiotherapy and chemotherapy.
Em
of GasExchange
Disturbances in the efficiency of carbon dioxide elimination and oxygen uptake frequently contribute to breathlessness by increasing ventilatory requirements. Conditions characterized by a high dead space (high V/Q) result in increased ventilation to achieve carbon dioxide elimination. Conversely, disorders leading to increased venous admixture (low V/Q) cause hypoxia, which further stimulates ventilation. The prototypic disorder that causes a high dead space to tidal volume ratio is pulmonary thromboembolism, which is treated with anticoagulation. While this is a well-described complication of malignancy, other pulmonary vascular diseases (such as tumor emboli, pulmonary hypertension) and parenchymal lung disorders also disturb V/Q relationships and reduce the efficiency of gas exchange. Under these circumstances, dyspnea may be ameliorated by the administration of supplemental oxygen to relieve hypoxia. The mode of administering the oxygen (either by nasal prongs or mask) is of secondary importance, as long as arterial oxygen saturation, monitored by arterial blood gases, or more simply by oximetry, is raised to greater than 90%. Although the relief of hypoxia is a rational indication for using oxygen, dyspneic patients with end-stage lung cancer are very often given oxygen without consideration of their arterial oxygen level, essentially as a form of palliation. In these situations, oxygen is likely to be of limited benefit.
Respiratory Muscles The degree of central motor output (and hence dyspnea) required to achieve adequate ventilation depends on both respiratory muscle strength and the impedance of the respiratory system. Respiratory muscle weakness and fatigue,
Journal of Pain and Symptom Management
due to several possible mechanisms, commonly contributes to breathlessness in patients with widespread cancer. Paraneoplastic syndromes are particularly frequent in primary lung cancer, and about 1% of patients manifest symptoms secondary to a neuropathic or myopathic syndrome at some point in their disease course. These include the Eaton-Lambert syndrome (predominantly due to small cell carcinoma), peripheral neuropathies, and dermatoand polymyositis. All of these conditions may involve the respiratory muscles, producing physiologically demonstrable respiratory muscle weakness, and often, clinically relevant dyspnea. Specific treatment directed at the respiratory muscles is usually not possible, but resolution of the paraneoplastic syndromes with treatment of the primary tumor has been documented. Respiratory muscle weakness may also be associated with the syndrome of anorexia and cachexia that is present in up to one third of lung cancer patients. Its etiology is unclear, but metabolic studies in noncachectic nonsmall cell lung cancer patients have demonstrated increased muscle catabolism.g A number of metabolic abnormalities may coexist in these patients, which can cause or aggravate preexisting weakness, including hypophosphatemia, hypocalcemia, and hypomagnesemia. This provides ample rationale for excluding and treating nutritional deficiencies in cancer patients, as they may worsen respiratory muscle weakness. Respiratory muscle weakness may also result from paralysis of a hemidiaphragm due to phrenic nerve involvement from intrathoracic spread of tumor. All of these problems coexist on a background of accelerating atrophy from disuse, which is secondary to reduced activation because of reduced activity. Assessment of respiratory muscle strength requires measurement of static maximum inspiratory and expiratory pressures. These simple maneuvers should be used to evaluate and follow patients with dyspnea and respiratory muscle weakness. Although there is a great deal of variability in these measurements among the general population, severe dyspnea is unlikely to ensue until they fall below 40 cm HsO. The demonstration of respiratory muscle weakness should prompt investigation to rule out neuropathic or myopathic paraneoplastic syndromes, cachexia, metabolic deficiencies, and diaphragmatic paralysis.
Vol. 4 No. 2 June I989
79
Dys@ea in Cancer Patients
Mechanical Efickncy of Respiratolr Muscles The ability of the respiratory muscles to generate pressure is reduced by inappropriate length-to-tension or force-to-velocity relationships. Breathlessness increases in situations where the inspiratory muscles are weakened by shortening their resting length, such as hyperinflation. lo Improvement in the operating characteristics of the muscle may occur with treatment of any reversible component (for example following bronchodilator therapy of the lung disease present), but this is often not feasible.
Impedance of the Respirahny System The majority of cancer patients are dyspneic because of increased impedance of the respiratory system due to increased airflow resistance, lung elastance, or a combination of both.
diation, surgical decompression, yag laser) or by systemic chemotherapy. Patients with localized airway obstruction, as well as generalized muscle weakness, often have difficulty clearing their secretions. Physiotherapy and aspiration of secretions may afford some symptomatic relief in these situations. Pleural effusions are a comEffusion. mon occurrence in intrathoracic malignancy, particularly with carcinomas of the lung and breast, or with lymphomas. Detection of a large pleural effusion should be followed by a therapeutic thoracentesis if the patient is dyspneic. Although a small number of patients will remain fluid-free after initial thoracentesis, in most the effusion recurs and consideration should be given to pleurodesis if a reasonable life span is anticipated and thoracentesis was effective in reducing breathlessness.‘*
Pleural
Both postobstructive pneumonia and pneumonia in areas remote from the sites of tumor cause breathlessness by increasing metabolic demands (pyrexia), altering gas exchange, and increasing pulmonary elastance. Diagnosis can usually be made from clinical presentation, chest radiograph, and sputum analysis. Breathlessness caused by pneumonia usually responds to appropriate antibiotics.
Znfection.
As the vast majority of primary lung cancers occur in smokers and roughly one fifth of smokers develop significant chronic airflow limitation, it is not surprising that many patients with lung cancer have symptomatic airflow limitation. This can be identified by simple spirometry (FEVJVC < 70%), or a flow volume loop. Treatment includes B2 adrenoreceptor agonists, theophylline derivatives, and inhaled or systemic corticosteroids,g which attempt to reverse diffuse airway obstruction. There is little rationale for withholding systemic corticosteroids in these patients because of concern over possible long-term sequelae. Steroids are often efficacious, affording considerable symptomatic relief in patients; in view of the expected short survival time, they should be used liberally. Localized airflow limitation due to upper airway obstruction (bilateral vocal cord paralysis; tumors of the pharynx, larynx, and thyroid), extrinsic compression (enlarged paratracheal or mediastinal nodes), or endobronchial tumor deposits are also common. Sites of localized obstruction may be suspected from the flow-tovolume curve which demonstrates cutoff of the inspiratory limb in variable extrathoracic obstruction, cutoff of the expiratory limb in variable intrathoracic obstruction, and a squaredoff appearance in fixed upper airway obstruction.” Reversal of localized obstruction may be achieved by specific local therapy (irra-
Aivjlow
Limitation.
Radiation
and
Drug-Znduced
Lung Disease.
Many of the therapeutic modalities used to treat malignancy may themselves cause lung damage and increase elastance. Radiation pneumonitis is diagnosed by a compatible clinical and radiographic presentation, and may respond to corticosteroids in the subacute phase, but is unlikely to do so in the chronic phase.13 Bleomycin, cyclophosphamide, methotrexate, and busulfan are among the many chemotherapeutic agents that can lead to pulmonary toxicity, causing primarily interstitial pneumonitis pathologically. They generally fail to respond to therapy, but a trial of corticosteroids is warranted, particularly if dyspnea is pronounced.14 Although these patients generally present with hypoxemia and radiographic infiltrates, frequently their presentation may be more subtle. The cancer patient with dyspnea and an apparently normal chest x-ray and arterial blood gases should still be thoroughly evaluated with pulmonary function testing, assessment of inspiratory muscle strength, gallium scanning,
80
Fishbein et al.
and, if indicated, an assessment of arterial oxygen saturation during exercise. Chest radiographs often are insensitive indicators of pulmonary involvement, and lag behind symptoms and pulmonary function tests, particularly the diffusing capacity. l5 The uptake of gallium by the lung is a nonspecific finding seen in several inflammatory diseases, but it may be an important clue to drug-induced lung disease.16 Similarly, arterial oxygen desaturation with exercise may reveal unsuspected gas exchange abnormalities. Lej Ventriculur Failure. Left ventricular failure, due to coexistent heart disease or as a complication of therapy, is also a relatively frequent event in patients with advanced cancer, and is treated in the same manner as in other patients, with diuretics, digoxin, and afterload reduction, depending on its severity. Lymphangitic Carcinomatosis. Among the most distressed and breathless of patients with widespread cancer are those with lymphangitic carcinomatosis, which can be suspected by its radiographic presentation (interstitial infiltrates associated with Kerley B lines) and confirmed, if necessary, by transbronchial biopsy. Although occasional improvements with systemic corticosteroids can be seen, these tend to be brief, and patients usually succumb within a short period of time, often with severe, unrelenting dyspnea. Progressive Intrathoracic Malignancy. Massive intraparenchymal tumors, primary or secondary, disorganize the lung, which decreases the efficiency of gas exchange and increases the impedance of the lung, resulting in central respiratory motor output sufficiently raised to produce dyspnea. Ultimately, treatment in this instance must be directed at the tumor itself, either with surgery, radiotherapy, or chemotherapy.
General Therapeutic P&ci.h Recognition of the factor or factors alone or in combination contributing to dyspnea is central to its successful management. As outlined in Figure 1, the various contributing factors all act in the final analysis by increasing central motor output. At each step in the paradigm, different processes impact, requiring different
Journal
oj Pain and Symptom Management
diagnostic and treatment strategies. This diagram will enable a systematic and organized approach to the investigation and treatment of the numerous causes of dyspnea in patients with advanced cancer. In some instances, therapy will have a clear beneficial effect on symptoms of breathlessness. However, all too often after completion of this evaluation and treatment of remediable conditions, one is left with a patient with advanced cancer with severe dyspnea, whose breathlessness is attributable to causes unresponsive to available specific treatment. The prospects for such patients are bleak and frequently their dyspnea persists unabated until their demise. In such a patient, treatment must leave the realm of therapy directed at a specific disease entity, and focus on pharmacotherapy intended to ameliorate the perception of breathlessness, rather than its cause. Studies to date have yielded conflicting results about the efficacy of various sedative narcotics in improving dyspnea. Most of these studies used benzodiazepines in modest doses.‘7-20 Such therapeutic conservatism is unwarranted in patients with advanced cancer and severe dyspnea, and in this situation opiates are a more appropriate choice. In addition to their anxiolytic effects, opiates decrease respiratory drive and lead to hypoventilation, and hence are efficacious in alleviating dyspnea. Morphine in judicious doses should therefore be used in patients with widespread cancer and intractable dyspnea not amenable to more specific therapy, to blunt the outgoing central motor command. In summary, we have presented a physiological approach to the management of dyspnea, which can be used as a framework for the categorization, evaluation and therapy of the numerous different conditions leading to breathlessness in patients with advanced cancer. This will allow the physician to determine if any condition amenable to therapy is responsible for the dyspnea and to proceed with appropriate therapy. Ultimately it should facilitate improved palliation of the severe, intractable dyspnea from which these patients often suffer.
References 1. Minna JD, Higgins GA, Glatstein EJ. Cancer of the lung. In: DeVita VT, Hillman S, Rosenberg SA, eds. Cancer-principles and practice of oncology, 2nd ed. Philadelphia: J.B. Lippincott, 1985:50’7-597.
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2. Willis RA. Pathology of tumors. ton-century Crofts, 1967:175.
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London:
3. Anonymous. The enigma of breathlessness. cet 1986;1:891-892. 4. Cherinack NS, Altose MD. Mechanisms pnea. Clin Chest Med 1987;8:207-214.
AppleLanof dys-
5. Killian KJ, Campbell EJM. Dyspnea. In: Roussos C, Macklem PT, eds. The thorax. New York: Marcel Decker, 1985:787-828. 6. Killian KJ, Campbell EJM. Dyspnea and exercise. Ann Rev Physiol 1983;45:465-479. 7. Tyler HR. Paraneoplastic syndromes of nerve, muscle and neuromuscular junction. Ann NY Acad Sci 1974;230:348-357. 8. Wilcox PC, Morrison NJ, Anzarut ARA, Pardy RL. Lambert-Eaton myasthenic syndrome involving the diaphragm. Chest 1988;93:604-606.
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12. Haushera FH, Yarbro JW. Diagnosis and treatment of malignant pleural effusion. Semin Oncol 1985;12:54-75. 13. Gross NJ. Pulmonary effects of radiation Ann Intern Med 1977;86:81-92.
therapy.
14. Cooper JAD, White DA, Matthay RA. Drug-induced pulmonary disease. Am Rev Respir Dis 1986;133:321-340. 15. Ginsberg SJ, Comis RL. The pulmonary toxicity of antineoplastic agents. Semin Oncol 1982;9:34-51. 16. Richman SD, Levinson SM, Bunn PA, et al. Gallium-67 accumulation in pulmonary lesions associated with eleomycin toxicity. Cancer 1975;36: 19661972. 17. Mitchell-Heggs P, Murphy K, Minty K, et al. Diazepam in the treatment of the “pink-puffer” syndrome. Q J Med 1980;49:9-20.
9. Hever D, Chelbowski RT, Ishibashi DE, Harrold JN, Block JB. Abnormalities in glucose and protein catabolism in noncachectic lung cancer patients. Cancer Res 1982;42:48 15-4819.
18. Woodcock AS, Gross ER, Gellent A, et al. Effect of dihydrocodeine, alcohol and caffeine in breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med 1981;305:1611-1616.
10. Killian KJ, Gandevia SC, Summers E, Campbell EJM. Effect of increased lung volume on perception of breathlessness, effort and tension. J Appl Physiol 1984;57:6866-6891.
19. Woodcock AA, Groos ER, Geddes DM. Drug treatment in breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Br Med J 1981;283:343-346.
11. Kryger M, Bode F, Antic R, Anthonisen N. Diagnosis of obstruction of the upper and central airways. Am J Med 1976;61:85-93.
20. Man CGW, Hsu K, Sproule BJ. Effects of alprazolam on exercise and dyspnea in patients with chronic obstructive disease. Chest 1986;90:832-836.