The Frequency and Correlates of Dyspnea in Patients with Advanced Cancer

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1 .357 Journal of Pain and Symptom Management Vol. 19 No. 5 May 2000 Original Article The Frequency and Correlates of Dyspnea in Patients with Advanced Cancer Eduardo Bruera, MD, Bonnie Schmitz, RRT, James Pither, RRT, Catherine M. Neumann, MSc, and John Hanson, MSc Department of Symptom Control and Palliative Care (E.B.), University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA, and Palliative Care Program (B.S., J.P., C.M.N., J.H.), Cross Cancer Institute, Division of Palliative Care Medicine, University of Alberta, Edmonton, Alberta, Canada Abstract Dyspnea is a devastating symptom in patients with advanced cancer. Unfortunately, very limited research has been done on the frequency and correlates of dyspnea in this particular patient population. The purpose of this prospective study was to assess the frequency of moderate to severe dyspnea and the correlates of dyspnea in a population of ambulatory terminally ill cancer patients. One hundred thirty-five consecutive patients attending a multidisciplinary pain clinic were tested for respiratory function (vital capacity, peak flow, maximal inspiratory pressure, and oxygen saturation). All patients gave their rating of dyspnea, anxiety, and fatigue/tiredness using visual analogue scales (VAS). Lung involvement by the tumor (primary or metastatic) was determined from the patient s chart. Moderate dyspnea occurred in 74/135 (55%) patients with terminal cancer. Lung involvement (r 0.285, P ), anxiety (r 0.306, P ), fatigue/tiredness (r 0.211, P ), and vital capacity (r 0.189, P ) were significantly correlated with the intensity of dyspnea. Multivariate analysis demonstrated that lung involvement (P ) and anxiety (P ) were independently correlated with the intensity of dyspnea. In the subgroup of patients with moderate to severe dyspnea, multivariate analysis found anxiety (P ) and maximal inspiratory pressure (P ) to be independent correlates of the intensity of dyspnea. Dyspnea is a frequent symptom in patients with advanced cancer. The presence of cancer in the lungs, anxiety, and maximal inspiratory pressure are correlates of the intensity of dyspnea in this patient population. Possible treatments addressing low maximal inspiratory pressure and anxiety are needed, as well as further research in finding new correlates of dyspnea in advanced cancer patients. J Pain Symptom Manage 2000;19: U.S. Cancer Pain Relief Committee, Key Words Cancer, dyspnea, symptom, palliative This data was presented, in part, at the 7th Canadian National Palliative Care Conference, Saskatoon, Saskatchewan, Address reprint requests to: Eduardo Bruera, MD, Director, Department of Symptom Control and Palliative Care, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Room P , Houston, TX 77030, USA. Accepted for publication: June 28, U.S. Cancer Pain Relief Committee, /00/$ see front matter Published by Elsevier, New York, New York PII S (00)

2 358 Bruera et al. Vol. 19 No. 5 May 2000 Introduction Dyspnea is a frequent and devastating symptom in patients with advanced cancer. 1 3 There is evidence that good symptom control, even by experienced palliative care teams, is achieved less frequently for dyspnea than for other symptoms such as pain or nausea. 4 One possible reason for this lack of therapeutic success is the very limited research conducted on the frequency and correlates of dyspnea in patients with advanced cancer. 5 In noncancer populations respiratory function tests have shown variable degrees of correlation with the intensity of dyspnea, ranging from highest in patients with asthma, to lower in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease. 6 8 A recent preliminary report in patients with cancer dyspnea found a high frequency of abnormal maximum inspiratory pressure (MIP), a measure of respiratory muscle impairment. 9 Unfortunately, the lack of a control group made the interpretation of these findings difficult. The purpose of this prospective study was to assess the frequency of moderate to severe dyspnea and the different correlates of dyspnea in a population of ambulatory terminally ill cancer patients. Methods One hundred forty-four consecutive patients referred to the Pain and Symptom Control Clinic, Cross Cancer Institute were included in this study. All patients had terminal cancer, described as locally recurrent or metastatic cancer, and were receiving no antineoplastic therapy with the purpose of cure or life prolongation. Patients were referred to the clinic by their primary physician, usually the medical or radiation therapist, for the management of different physical and psychosocial symptoms associated with advanced cancer. Patients were assessed between April 1996 and March Nine patients were not included because of severe pain that precluded a dyspnea assessment, lack of time to complete the assessment, or other reasons. As part of their initial assessment during their clinic visit, all patients completed the following assessments: 1. Intensity of dyspnea: a visual analogue scale (VAS) was completed. Patients were asked to rank their intensity of dyspnea that day from 0 (no shortness of breath) to 100 (worst possible shortness of breath). In all cases the VAS was presented as a horizontal line. This method has been used by a number of authors in the past Based on our previous experience with multiple symptom complaints in patients with advanced cancer, and similar experience in cases of pain assessment, 13 dyspnea of at least moderate intensity was defined as an intensity of more than or equal to 30/100 in the VAS. Those scoring 30/100 were used as a control group representing patients in whom dyspnea was not a clinical problem. We chose this method instead of a cutoff of value of 0 because many patients who would answer no to the question: Do you have dyspnea? would score the VAS as 0/ VAS from 0 (best) to 100 (worst) were completed for anxiety and fatigue/tiredness. The term fatigue was changed to tiredness to be consistent with the term being used in other parts of the Edmonton Regional Program. Twenty-eight of the 135 patients were assessed for tiredness. 3. Respiratory function tests: Vital capacity, peak flow, and MIP were determined in all patients. Results were expressed as a percentage of the normal expected value based on age and gender for vital capacity and peak flow, and in cm H 2 O for MIP. Oxygen saturation after at least 30 minutes rest was established by pulse oximetry. 4. In all cases the presence of tumor involvement of the lung was determined from the chart. In cases in which the intensity of dyspnea was scored as 30/100 and there had been no recent (i.e. 2 weeks) investigations in the chart, a chest radiograph was performed to assess pulmonary involvement by tumor. Lung involvement was defined as evidence for the presence of recurrent local tumor with or without evidence of collapse or consolidation, mediastinal or hilar adenopathy, metastatic lung disease, carcinomatous lymphangitis, or pleural effusion. Statistical Analysis Results were expressed as median (interquartile range). Comparisons of symptom in-

3 Vol. 19 No. 5 May 2000 Frequency and Correlates of Dyspnea 359 tensity or difference in respiratory function test results (Table 1) were analyzed using Kruskal-Wallis test for nonparametric data. Comparisons between other results, such as the presence of lung involvement or presence or absence of different symptoms or respiratory abnormalities were analyzed using Chisquared tests (Table 2) Finally the association between different variables and the intensity of dyspnea, both for the overall population and the population with dyspnea, were determined using univariate and multivariate correlation (Table 3). In all cases, data were analyzed using the SAS statistical package. 14 Results Characteristics of the 135 evaluable patients are summarized in Table 4. Moderate dyspnea occurred in 74/135 (55%) patients. Only 33 patients (24%) completed their shortness of breath VAS as 0/100. Table 1 summarizes the median patient scores. Both the intensity of dyspnea and anxiety were significantly higher in those patients defined as having moderate dyspnea. Fatigue/tiredness was the most severe symptom [median 60 (40 80)], although its intensity was not significantly higher among those patients who complained of dyspnea. Table 2 summarizes the frequency of abnormal scores and lung involvement in patients with and without moderate dyspnea. Respiratory function tests were frequently abnormal both in dyspneic and nondyspneic patients. Only vital capacity was more frequently abnormal among patients with moderate dyspnea. Both lung involvement and anxiety were more frequent among patients with moderate dyspnea. Table 3 summarizes the univariate and multivariate correlations between the intensity of dyspnea and different variables in both the overall population and the population with dyspnea 30/100. Lung involvement, anxiety, fatigue/tiredness, and vital capacity were significantly correlated with the intensity of dyspnea in the overall population. MIP showed borderline (P 0.07) correlation. Multivariate analysis showed that lung involvement and anxiety were independently correlated with the intensity of dyspnea. A similar trend was found for MIP (P ). Multivariate analysis in patients with moderate to severe dyspnea ( 30/100) found that anxiety and MIP were independent correlates of the intensity of dyspnea. Vital capacity was not entered into the multivariate model because there were 22 missing values. This is mostly because patients were not able to appropriately complete the test due to pain, dyspnea, or other symptoms. Table 5 summarizes the univariate correlations between all of the measured characteristics, symptoms, and respiratory function test scores. Discussion Seventy-four (55%) of the patients in our study rated their dyspnea as 30/100. The high prevalence of dyspnea coincides with other studies, which report values ranging from 21% to 70% of patients with advanced cancer. Our findings suggest that the limit of 30/ 100 appropriately differentiated a population with a median dyspnea VAS score of 50 (50 70) from a population with a median dyspnea VAS score of 0 (0 10) (Table 1). The experience of our group 15 and others 16 suggest that advanced and terminal cancer patients very rarely describe total absence of many symp- Variable Table 1 Patient Symptom and Respiratory Function Test Scores a All Patients Yes (30 ) (n 74) Dyspnea No ( 30) (n 61) P Value Dyspnea (VAS) 30 (10 60) 50 (50 70) 0 (0 10) Anxiety (VAS) 30 (20 60) 50 (20 60) 30 (10 50) Fatigue/tiredness (VAS) 60 (40 80) 60 (50 80) 60 (40 80) Vital capacity (% predicted) 76 (62 89) 69.5 (59 88) 80 (65 90) Peak flow (% predicted) 59 (41 81) 59 (40 80) 59 ( ) Maximal inspiratory pressure (cm H 2 O) 58 (36 80) 54 (35 80) 60 (38 80) O 2 saturation (%) 95 (94 97) 95 (94 97) 95 (94 97) a Results are expressed as median (interquartile range).

4 360 Bruera et al. Vol. 19 No. 5 May 2000 Table 2 Frequency of Abnormal Scores and Lung Involvement in Patients With and Without Dyspnea Variable Dyspnea Yes ( 30/100) No ( 30/100) P Value Lung involvement 44/73 (60%) 19/59 (32%) Anxiety 30/100 VAS 51/73 (70%) 31/61 (51%) Fatigue/tiredness 30/100 VAS 67/73 (92%) 52/61 (85%) Vital capacity 80% predicted 42/62 (68%) 24/51 (47%) Peak flow 80% predicted 52/71 (73%) 43/60 (72%) MIP 60 cm H 2 O 38/70 (54%) 28/60 (47%) O 2 saturation 95% 27/71 (38%) 19/61 (31%) toms. Unfortunately, there has been limited research as to what can be interpreted as moderate to severe intensity requiring aggressive pharmacological or nonpharmacological interventions. Our decision to use a cutoff intensity of 30/100 was based on the good correlation found between VAS and other dyspnea tests, 8,10,11 as well as studies done in the assessment of symptoms such as pain. 13 Major impairment in function and quality of life due to a specific symptom appears to be detected within intensity values of 30% of the maximum, and increase sharply when those values exceed 50% of the maximum. 8,10,11,13,16 Lung involvement was significantly associated with the presence and intensity of dyspnea (Tables 2 3). However, in patients with moderate to severe dyspnea, lung involvement was not found to be an independent correlate for the intensity of dyspnea (Table 3). These findings suggest that the simple characterization of lung involvement as present or absent is not a good predictor of severity of dyspnea in patients who complain of moderate to severe dyspnea. In the future, better characterizations of the severity of lung involvement may be required. Our findings suggest that neither the level of obstruction to air flow (peak flow) nor the O 2 saturation level is a predictor for the presence or severity of dyspnea. Unfortunately, the overall vital capacity could not be entered in the multivariate model, mostly because 22 patients were not able to appropriately complete this test. These findings suggest that even if vital capacity was to be found to be a predictor of intensity of dyspnea, it may not be a very practical tool in patients with terminal cancer because a large proportion of this ambulatory patient population was not able to complete this test. Other authors have found that vital capacity significantly correlated with dyspnea in patients with some conditions such as asthma, whereas the correlation is poor in other conditions such as chronic obstructive pulmonary disease and interstitial lung disease. 6 Our results confirm those reported by Dudgeon and Lertzman regarding the independent association between MIP and intensity of dyspnea. 9 Our findings suggest that respiratory muscle weakness is one of the independent correlates of the intensity of dyspnea, both in Variable Table 3 Correlations Between the Intensity of Dyspnea and Different Variables a Univariate correlation in all patients (r,p) Multivariate correlation in all patients (p) Multivariate correlation in patients with dyspnea 3 (p) Lung involvement , Anxiety , Fatigue/tiredness , Vital capacity , not in model Peak flow , not in model MIP , O 2 saturation , not in model Age , not in model Gender , not in model a Vital capacity was not entered into the model because there were 22 missing values.

5 Vol. 19 No. 5 May 2000 Frequency and Correlates of Dyspnea 361 Table 4 Patient Characteristics Age (mean SD) Gender, M/F 69/66 Tumor Lung 35 Breast 26 GI 24 GU 18 Melanoma 6 Hematological 5 Head and neck 4 Other 17 Total 135 Lung involvement 63/132 (48%) the overall population and in the subgroup of patients with moderate to severe dyspnea. Similar results were reported in COPD patients. 17 However, the correlation between MIP and dyspnea in the overall patient population of our study was not very strong. A low MIP, indicating a possible weakness of inspiratory muscles, could not be universally equated with dyspnea. Clinical trials with drugs likely to increase inspiratory muscle strength may benefit terminal cancer patients with moderate to severe dyspnea. In patients with congestive heart failure, nasal continuous positive airway pressure, which improves inspiratory muscle strength, had positive effects on dyspnea. 18 Interestingly, there is no correlation between MIP and fatigue/tiredness, indicating that inspiratory muscle weakness is not necessarily related to subjective asthenia. While fatigue/tiredness is univariately correlated to dyspnea, it is no longer significant in our multivariate model. The strong univariate correlation between fatigue/tiredness and anxiety suggests that a large part of the interaction between fatigue/tiredness and dyspnea can be explained by the interaction between anxiety and fatigue/tiredness. Anxiety is strongly correlated with dyspnea both in our overall population and in the subpopulation of patients with dyspnea 30/100. This correlation is difficult to interpret, as anxiety may contribute to dyspnea, but may also be caused by dyspnea. Clinical trials to pharmacologically reduce dyspnea by treating anxiety have met with little success, indicating that anxiety may not be a direct cause of dyspnea. 3 However, studies using nonpharmacological interventions to reduce anxiety in dyspneic pa- Table 5 Univariate Correlations Between All of the Measured Characteristics, Symptoms, and Respiratory Function Tests Lung involvement Age Gender MIP Peak flow O 2 saturation Fatigue/ tiredness Anxiety Vital capacity Age r P n 132 Gender r P n.s n.s n MIP r P n.s. n.s n Peak/flow r P n.s. n.s n O 2 Saturation r P n.s. n.s n.s n Fatigue/tiredness r P n.s. n.s. n.s. n.s. n.s. n.s. n Anxiety r P n.s. n.s. n.s. n.s. n.s n Vital capacity r P n.s n.s. n.s. n Shortness of breath r P n.s n.s n

6 362 Bruera et al. Vol. 19 No. 5 May 2000 tients have had some success. 19,20 Further research is needed to clarify the complex relationship between anxiety and dyspnea. Our multivariate model accounted for only 18% of the variation in dyspnea scores. Clearly there are other factors that contribute to the sensation of dyspnea. Dyspnea is a complicated symptom, which is influenced on many levels, including the respiratory center in the medulla and the brain cortex. It is very difficult to quantify the events at these levels. In addition, dyspnea is a subjective symptom, and can be influenced by intrapsychic or cultural factors, and the patients beliefs. 3 Therefore, the patients own assessment of their dyspnea is very important, as it is the only complete measure that can be clinically obtained. This study did not look at pleural pressure, or FEV 1, both of which have been correlated with dyspnea and should be included in future studies. Future studies should also look at the involvement of chronic pulmonary disease, cardiac disease, pulmonary embolism, and the medications received by the patient in dyspnea. We conclude that lung involvement, anxiety, and MIP all influence the intensity of dyspnea in advanced cancer patients. More studies are required in order to better characterize these associations and the role of different interventions aimed at anxiety (pharmacological or nonpharmacological) or respiratory muscle strength (such as theophylline or clenbuterol) in dyspnea. Research should also focus on the identification of new correlates that might help to better understand why cancer patients perceive such wide variation in the intensity of this devastating symptom. References 1. Ahmedzai S. Palliation of respiratory symptoms. In: Doyle D, Hanks GWC, MacDonald N, eds. Oxford textbook of palliative medicine. Oxford: Oxford University Press, 1993;4: Cowcher K, Hanks GW. Long-term management of respiratory symptoms in advanced cancer. J Pain Symptom Manage 1990;5: Bruera E, Ripamonti C. Dyspnea in patients with advanced cancer. In: Berger A, et al., eds. Principles and practice of support oncology. Philadelphia: Lippincott-Raven, 1998;23: Higginson I, McCarthy M. Measuring symptoms in terminal cancer: are pain and dyspnoea controlled? J Royal Soc Med 1989;82: Davis CL. The therapeutics of dyspnoea. Cancer Surveys 1994;21: Mahler DA, Harver A. Clinical measurement of dyspnea. In: Mahler DA, ed. Dyspnea. Mount Kisco, NY: Futura, 1990: Ferrari K, Goti P, Misuri G, Amendola M, Rosi E, Grazzini M, et al. Chronic exertional dyspnea and respiratory muscle function in patients with chronic obstructive pulmonary disease. Lung 1997;175: Killian KJ, Jones NL. Respiratory muscles and dyspnea. Clinics Chest Med 1988;9: Dudgeon D, Lertzman M. Etiology of dyspnea in advanced cancer patients. Proc ASCO 1996;15: Lush MT, Janson-Bjerklie S, Carrieri VK, Lovejoy N. Dyspnea in the ventilator-assisted patient. Heart Lung 1988;17: Wilson RC, Jones PW. A comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnoea during exercise. Clin Sci 1989;76: Gift AG. Validation of a vertical visual analogue scale as a measure of clinical dyspnea. Rehab Nurs 1989;14: Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimetres. Pain 1997;72: SAS Institute Inc. Cary, NC. V6.12. copyright Bruera E, MacDonald S. Audit methods: the Edmonton Symptom Assessment System. In: Higginson I, ed. Clinical audit in palliative care. Oxford, UK: Radcliffe Medical Press, 1993: Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23: Mancini M, Rosi E, Scano G. Breathlessness and control of breathing in patients with COPD. Monaldi Arch Chest Dis 1997;52: Granton JT, Naughton MT, Benard DC, Liu PP, Goldstein RS, Bradley TD. CPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1996;153: Corner J, Plant H, A Hern R, Bailey C. Nonpharmacological intervention for breathlessness in lung cancer. Palliat Med 1996;10: Filshie J, Penn K, Ashley S, Davis CL. Acupuncture for the relief of cancer-related breathlessness. Palliat Med 1996;10: