Descriptors of Breathlessness in Patients With Cancer and Other Cardiorespiratory Diseases

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1 182 Journal of Pain and Symptom Management Vol. 23 No. 3 March 2002 Original Article Descriptors of Breathlessness in Patients With Cancer and Other Cardiorespiratory Diseases Andrew Wilcock, DM, FRCP, Vincent Crosby, MRCGP, Andrew Hughes, MRCGP, Katherine Fielding, PhD, Ray Corcoran, FRCOG, and Anne E. Tattersfield, MD, FRCP Department of Palliative Medicine (A.W., V.C., R.C.), Hayward House Macmillan Specialist Palliative Care Unit, and Department of Respiratory Medicine (A.E.T.), University of Nottingham, Nottingham City Hospital NHS Trust, Nottingham; St. Oswald s Hospice (A.H.), Newcastle-upon-Tyne; and Department of Infectious and Tropical Diseases (K.F.), London School of Tropical Medicine, London, United Kingdom Abstract The objective of this study was to examine the relationship between descriptors of breathlessness and its underlying cause in patients with lung cancer and cardiopulmonary diseases to see whether descriptors might be used to help determine the cause of breathlessness, particularly in patients with lung cancer. We studied 131 patients with primary or secondary lung cancer, whose breathlessness was attributed to tumor mass, pleural effusion, lung collapse, metastases, pleural thickening or lymphangitis carcinomatosis, and 130 patients with breathlessness attributed to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease or cardiac failure. Patients selected statements (descriptors) that described the quality of their breathlessness from a 15-item questionnaire and the relationship between the descriptors and the attributed cause of breathlessness was evaluated by cluster analysis. All patient groups were characterized by more than one cluster and several clusters were shared between groups. Specific sets of clusters were associated with breathlessness due to asthma, COPD and cardiac failure, and to cancer causing collapse, metastases or pleural thickening. The association of different sets of clusters with the different diagnostic groups suggests that patients are describing qualitatively different experiences of breathlessness, but the relationship does not appear to be sufficiently robust for the questionnaire to aid differential diagnosis. J Pain Symptom Manage 2002;23: U.S. Cancer Pain Relief Committee, Key Words Breathlessness, dyspnea, descriptors, cancer, cardiorespiratory diseases, qualitative Address reprint requests to: Andrew Wilcock, DM FRCP, Department of Palliative Medicine, Hayward House Macmillan Specialist Palliative Care Unit, Nottingham City Hospital NHS Trust, Nottingham NG5 1PB, United Kingdom. Accepted for publication: July 11, Introduction Breathlessness has been defined as an unpleasant or uncomfortable awareness of the need to breathe. 1 Patients use a host of different words and phrases to describe their sensation of breathlessness. For example, it is frequently described as a tightness by patients with asthma and as suffocating in those with left ventricular failure. How the different de- U.S. Cancer Pain Relief Committee, /02/$ see front matter Published by Elsevier, New York, New York PII S (01)

2 Vol. 23 No. 3 March 2002 Qualitative Aspects of Breathlessness 183 scriptors relate to the underlying pathophysiology has been studied in healthy volunteers made breathless by various means and in patients with chronic cardiorespiratory conditions. 2-5 Patients with different cardiorespiratory conditions appear to experience breathlessness that varies qualitatively and it has been suggested that this may be of use in differential diagnosis. 5 A better understanding of how descriptors relate to the underlying pathology may help target therapies more appropriately, particularly in patients with conditions such as cancer. The aim of this study was to obtain descriptions of breathlessness from patients with lung cancer and chronic cardiorespiratory diseases using a set of 15 descriptors derived from previous studies. 3, 5 The relationship between the descriptors and the attributed cause of breathlessness was evaluated by cluster analysis, a technique that groups items associated with one another into clusters on the basis of the variance between items, which is minimal within and maximal between clusters. Methods Patients Patients were recruited from general, respiratory, cardiology, oncology and palliative care inpatient and outpatient wards and clinics. All patients had had a recent chest radiograph. Patients for whom English was not a first language were excluded. Activities of daily living were restricted because of breathlessness in all patients. All gave verbal informed consent and the study was approved by the Nottingham City Hospital Ethics Committee. Patients with Lung Cancer. All patients with lung cancer had an increase in breathlessness since their diagnosis of cancer and were divided into six groups depending on the predominant pathological feature on their chest radiograph which was thought to be responsible for their worsening breathlessness: (1) tumor mass, (2) pleural effusion, (3) collapse of a lobe(s) or lung, (4) metastases, (5) pleural thickening and (6) lymphangitis carcinomatosis. Patients with two or more pathological features which were thought to be responsible for their worsening breathlessness were excluded. Those with coexistent chronic obstructive pulmonary disease (COPD) were included if their COPD was clinically stable and not considered to be responsible for their recent increase in breathlessness. Patients with Nonmalignant Cardiorespiratory Disease. Patients with asthma, COPD, interstitial lung disease and cardiac failure were studied. The characteristics of the four groups were: 1. Asthma. All patients had a history of wheeze, breathlessness or cough attributed to asthma. Thirty-one of the 37 patients had demonstrated an increase in FEV 1, either greater than 9% of predicted FEV 6 1 or 300 ml, with bronchodilators or following a trial of corticosteroid therapy. In the remaining 6 patients, no formal test of reversibility was documented in the hospital records but asthma was considered to be the cause of their breathlessness. 2. COPD. All patients were current or ex-smokers with a productive cough and breathlessness attributed to COPD. Twenty-five of the 34 patients failed to demonstrate an increase in FEV 1, either greater than 9% of predicted FEV 6 1 or 300ml, with bronchodilators or following a trial of corticosteroids. In the remaining 9 patients, no formal test of reversibility was documented in the hospital records but COPD was considered to be the cause of their breathlessness. 3. Interstitial lung disease. All patients had bilateral pulmonary infiltrates on the chest radiograph and either a lung biopsy confirming the diagnosis or lung function tests indicating a restrictive defect with reduced lung volumes and transfer factor for carbon monoxide. 4. Cardiac failure. Patients had radiographic evidence of cardiomegaly with pulmonary venous congestion and/or impaired left ventricular function on echocardiography. Protocol The questionnaire consisted of an introductory statement explaining the purpose of the study and the list of 15 descriptors of breathlessness used by Simon et al. 3 (Table 1). Patients were instructed to choose any number of descriptors which they felt helped to describe their experience of breathlessness. They were then asked to rank the three descriptors

3 184 Wilcock et al. Vol. 23 No. 3 March 2002 which best described their breathlessness. No prompting or guidance was given. Statistical Analysis A one-way analysis of variance (ANOVA) was used to examine differences in age and the number of descriptors chosen by each patient in each group and in FEV 1, FEV 1 % predicted and FEV 1 /FVC% in the patients with asthma, COPD and interstitial lung disease. When a significant difference was found on ANOVA, unpaired t-tests were carried out using Bonferroni s correction to allow for multiple testing. Because there are no agreed criteria to determine how descriptors should be grouped, we used the same cluster analysis and criteria as Mahler et al. 5 to allow our results to be compared with theirs. The degree of association between descriptors for all subjects was assessed by the K-means cluster analysis which involves an iterative process based on a prespecified number of clusters: In this study, k was set to 10 as previously. 5 An additional analysis that used a hierarchical procedure involving the average linkage method was carried out to provide a visual representation (dendrogram) of the links among clusters. 5 The association between a cluster and an underlying condition was assessed by the number of times a descriptor within each cluster was chosen as one of the best three for a particular condition divided by the product of the number of descriptors in the cluster and the number of patients with the condition. A cluster Table 1 The 15 Descriptors of Breathlessness Contained in the Questionnaire, Presented in Random Order 1. I feel that my breathing is rapid. 2. My breath does not go out all the way. 3. My breath does not go in all the way. 4. My breathing is shallow. 5. My breathing requires effort. 6. My breathing requires more work. 7. I feel that I am smothering. 8. I feel that I am suffocating. 9. I feel hunger for more air. 10. I feel out of breath. 11. I cannot get enough air. 12. My chest feels tight. 13. My chest is constricted. 14. My breathing is heavy. 15. I feel that I am breathing more. met the criterion for association when a value greater than 0.25 was obtained. 3, 5 Cluster analyses were carried out using the Statistical Package for Social Scientists software for Windows, version 6.1. A p-value 0.05 was regarded as being statistically significant. Results The concept was easily understood by patients and questionnaires took less than 5 minutes to complete. The 261 patients (160 male/ 101 female) recruited had a mean SD age of years. Patient characteristics are described in Table 2. Patients with Cancer Of the 131 patients with cancer affecting the lung, the main factor contributing to breathlessness was considered to be: 1. Tumor mass (n 37) Of these, 34 had primary lung cancer and three had a solitary metastasis. Thirty patients had a central mass, six had a peripheral mass and one had tumor replacing the whole of one lung. Eleven patients also had COPD. 2. Pleural effusion (n 28) Twenty had primary lung cancer and the remainder had metastatic disease. Six patients had bilateral effusions and two had COPD. 3. Collapse (n 23) All had primary lung cancer. Fifteen patients had partial or complete collapse of one or two lobes and eight had complete collapse of one lung. Collapse was due to extrinsic compression from a centrally placed tumor in twelve patients and to endobronchial disease in eleven. Five patients also had COPD. 4. Metastases (n 21) All had metastases in both lungs; three also had COPD. 5. Pleural thickening (n 11) Six had carcinoma of the bronchus and five had metastatic disease; one patient had COPD. 6. Lymphangitis carcinomatosis (n 11) This was due to carcinoma of the breast, bronchus or prostate; one patient had COPD. Twenty-four and eight patients were receiving regular opioid or benzodiazepine medication, respectively.

4 Vol. 23 No. 3 March 2002 Qualitative Aspects of Breathlessness 185 Table 2 Mean ( SD) Characteristics of Patients According to Diagnosis Lung Cancer Lymphangitis Carcinomatosis Pleural Thickening Cardiac Failure Tumor Mass Pleural Effusion Collapse Metastases Interstitial Lung Disease Disease Asthma COPD No. of patients Sex: M/F 19/18 22/12 21/8 20/10 25/12 15/13 15/8 13/8 7/4 3/8 Age (years) FEV1 (litres) FEV1% predicted FEV1/FVC% TLCO% predicted No. of descriptors chosen COPD chronic obstructive pulmonary disease. FEV1 forced expiratory volume in one second. FEV1% predicted percent predicted forced expiratory volume in one second. FEV1/FVC% percentage ratio of forced expiratory volume in one second to forced vital capacity. TLCO% predicted percent predicted transfer factor for carbon monoxide. Patients with Nonmalignant Cardiopulmonary Disease Of the 130 patients, 37 had asthma, 34 had COPD, 29 had interstitial lung disease (20 with cryptogenic fibrosing alveolitis and three each with extrinsic allergic alveolitis, sarcoidosis and rheumatoid lung), and 30 had cardiac failure (28 ischemic heart disease). One and two patients were receiving regular opioid or benzodiazepine medication, respectively. Age, FEV 1 % predicted, and FEV 1 /FVC% differed significantly between the three groups of patients with chronic respiratory disease (ANOVA, p ); this was because the patients with asthma were younger, the patients with COPD had a lower FEV 1 % predicted, and those with interstitial lung disease had a higher FEV 1 / FVC% (all p 0.001). Descriptors/Clusters The mean SD number of descriptors chosen by the 261 patients was (range 1 to 15). The mean number of descriptors chosen ranged from 5.5 in the lymphangitis group to 8.4 in the COPD group, with no significant difference between groups (p 0.11). Best Three Descriptors All but 13 patients were able to provide their best three descriptors. Table 3 lists the descriptors selected most frequently as one of the best three within each patient group. The descriptor I cannot get enough air was common to all patient groups. Cluster Analyses The 10 clusters obtained by the K-means analysis are listed in Table 4. Five clusters had one descriptor and five contained two described as rapid/heavy, exhalation/inhalation, work/effort, suffocating/smothering and tight/constricted. The dendrogram resulting from the hierarchical procedure is shown in Figure 1. Relation of Clusters to Disease The relationship between the 10 clusters and the different patient groups is shown in Table 5. All groups were characterized by more than one cluster. The cluster enough air was associated with all patient groups and out of breath with all but one (COPD). Four clusters

5 186 Wilcock et al. Vol. 23 No. 3 March 2002 Patient Group Table 3 Descriptors Selected Most Frequently by Each Patient Group Descriptor Nonmalignant cardiorespiratory disease Asthma My chest feels tight. (54%) (n 37) I cannot get enough air. (32%) My breathing requires effort. (30%) I feel out of breath. (30%) COPD I cannot get enough air. (44%) (n 34) I feel hunger for more air. (38%) My chest feels tight. (29%) Interstitial lung I feel out of breath. (62%) disease I cannot get enough air. (45%) (n 29) My breathing is rapid. (28%) Cardiac failure I feel out of breath. (57%) (n 30) My chest feels tight. (33%) I cannot get enough air. (33%) Lung cancer Tumor mass I cannot get enough air. (51%) (n 37) I feel out of breath. (43%) My breathing requires effort. (30%) Pleural effusion I feel out of breath. (61%) (n 28) I cannot get enough air. (50%) My breathing is rapid. (29%) Lobar or I cannot get enough air. (47%) lung collapse I feel out of breath. (39%) (n 23) My breathing is shallow. (26%) Metastases I feel out of breath. (43%) (n 21) I cannot get enough air. (38%) My breathing requires work. (24%) My chest feels tight. (24%) I feel that I am breathing more. (24%) Pleural I feel out of breath. (45%) thickening My chest feels tight. (45%) (n 11) I feel hunger for more air. (36%) I cannot get enough air. (36%) Lymphangitis My breathing requires effort. (36%) carcinomatosis My breathing requires work. (36%) (n 11) I feel out of breath. (36%) I cannot get enough air. (36%) Table 4 Clusters and Descriptors From K-Means Analysis Cluster Name Descriptor 1. Rapid/Heavy 1. My breathing is rapid. 14. My breathing is heavy. 2. Exhalation/Inhalation 2. My breath does not go out all the way. 3. My breath does not go in all the way. 3. Shallow 4. My breathing is shallow. 4. Work/Effort 5. My breathing requires effort. 6. My breathing requires work. 5. Suffocating/Smothering 7. I feel that I am smothering. 8. I feel that I am suffocating. 6. Hunger 9. I feel hunger for more air. 7. Tight/Constricted 12. My chest feels tight. 13. My chest is constricted. 8. Enough air 11. I cannot get enough air. 9. Out of breath 10. I feel out of breath. 10. Breathing more 15. I feel that I am breathing more. were associated with four, three or two patient groups: tight/constricted with pleural thickening, asthma, COPD and cardiac failure; work/ effort with tumor mass, lymphangitis carcinomatosis and asthma; hunger with pleural thickening and COPD; rapid/heavy with pleural effusion and interstitial lung disease. Shallow was only associated with patients with lobar or lung collapse. The clusters exhalation/inhalation, suffocating/smothering and breathing more were not associated with any conditions. The same combinations of clusters were shared between the pleural effusion and interstitial lung disease groups ( rapid/heavy, enough air and out of breath ) and between the tumor mass and lymphangitis groups ( work/ effort, enough air and out of breath ) respectively. The other conditions were associated with different combinations of clusters. The number in parentheses represents the percentage of patients who selected that descriptor as one of their best three. Fig. 1. Dendrogram resulting from the hierarchial cluster analysis of descriptors of breathlessness in 261 patients. Moving from left to right, the shorter the distance is before the descriptors combine, the more similar they are. For key to descriptors see Table 4.

6 Vol. 23 No. 3 March 2002 Qualitative Aspects of Breathlessness 187 Table 5 Relationship Between Clusters of Descriptors and Disease Groups a Lung Cancer Lymphangitis Carcinomatosis n 11 Pleural Thickening n 11 Metastases n 21 Collapse n 23 Pleural Effusion n 28 Tumor Mass n 37 Cardiac Failure n 30 Interstitial Lung Disease n 29 COPD n 34 Asthma n 37 Cluster Name Descriptor 1. Rapid/Heavy 1,14 * * 2. Exhalation/Inhalation 2,3 3. Shallow 4 * 4. Work/Effort 5,6 * * * 5. Suffocating/Smothering 7,8 6. Hunger 9 * * 7. Tight/Constricted 12,13 * * * * 8. Enough air 11 * * * * * * * * * * 9. Out of breath 10 * * * * * * * * * 10. Breathing more 15 a The cluster was considered to characterize a particular diagnostic group if a value greater than 0.25 was obtained when the number of times the descriptors were chosen among the best three by the patients was divided by the product of the number of times a descriptor from that cluster was among the best three and the number of patients with the condition. For key to descriptors, see Table 4. Discussion This is the first time the 15-item questionnaire developed by Simon et al. 2,3 has been used in British patients and in patients with breathlessness due to cancer. The questionnaire was acceptable to patients and easy to complete. We adapted the methodology developed in patients with chronic non-malignant disease, which used a questionnaire that initially had 19 items and then 15 items. 3,5 The 15-item questionnaire produced clusters which appeared to provide a more discriminating association with the underlying conditions. 3,5 Cluster analysis arranged the 15 descriptors into 10 clusters, five of which contained two descriptors. Four of the five pairings were unsurprising (e.g., my chest feels tight with my chest is constricted ), whereas the pairing of my breathing is rapid with my breathing is heavy was less understandable. Each pathophysiological condition was associated with more than one cluster and six of the 10 diagnostic groups had different combinations of clusters. This suggests that patients are reporting qualitatively different experiences of breathlessness. Patients with Cancer In four of the six groups of patients with lung cancer, the clusters formed specific patterns of association suggesting that breathlessness varies qualitatively according to the underlying cause of breathlessness. However, the degree of overlap in the clusters between groups and the relatively low proportion of patients selecting the descriptors within each group suggests that the descriptors are insufficiently discriminating to be of use in differential diagnosis. There are potential difficulties in trying to ascribe the cause of breathlessness in patients with cancer compared with patients with nonmalignant cardiorespiratory disease. The clinical assessment of the pathological feature most likely to be responsible for their increasing breathlessness is not an exact science and other factors may have contributed to breathlessness in some patients, including COPD. There was however, little overlap between the clusters associated with the COPD group and the tumor mass group, the group with the greatest proportion of patients with coexistent COPD (30%). Further, the clusters for the tumor mass group

7 188 Wilcock et al. Vol. 23 No. 3 March 2002 were unchanged when analyzed with the patients with coexisting COPD excluded. A quarter of the patients were taking opioids and benzodiazepines, which also might affect the qualitative experience of breathlessness. Future studies also need to examine if the extent of the underlying disease process (e.g., size of pleural effusion) or the severity of breathlessness affects the choice of descriptors. Nonmalignant Cardiopulmonary Disease In the four nonmalignant disease patient groups, the clusters formed specific patterns of association suggesting that breathlessness differed qualitatively with the underlying cause of breathlessness. Our findings differ in some respects from those of Mahler et al., 5 however, despite using the same 15-item questionnaire and analysis. Comparison of Tables 3 and 7 shows some similarities but several differences in the best three descriptors chosen by patients in our study and that of Mahler et al. Of the 10 clusters only five were identical and each disease group was associated with a different pattern of clusters in the two studies (Tables 5 and 6). Such differences are not perhaps surprising considering the cultural differences in the use and understanding of words between a North American and British population. The American patients chose a greater number of descriptors than the British (group mean 10.0 compared to 6.7 respectively). When British doctors, nurses or patients have tried to develop a breathlessness assessment questionnaire for British patients they judged some of the descriptors used by Simon et al. 2 to be unsuitable or failed to produce similar descriptors of breathlessness. 4,7,8 These include descriptors relating to work or effort of breathing, which are among the most popular choices of American patients. 2,3,5 Socio-economic and educational backgrounds also affect the use of language but were not examined and cannot be compared. There were some differences in selection criteria used and this may also account for some of the difference between the findings of Mahler et al. and ourselves. The number of patients within each group also varied in the two studies. For example, we had twice as many patients with heart failure, but half as many with COPD. There may also be some differences in the severity of the patients breathlessness in the two studies. The extent to which the choice of descriptors is influenced by the severity of breathlessness and/or the underlying disease process is unclear and needs to be studied further. 2,3,5,9 Implications of Our Findings Although the association of different descriptors and clusters with different diagnostic groups suggests that patients are describing qualitatively different experiences of breathlessness, it is difficult to identify relationships that demonstrate construct validity and sufficient robustness to be of help in differential diagnosis. The proportion of patients selecting the most popular descriptor within a group never exceeded 62% ( I feel out of breath; interstitial lung disease group). How patients use descriptors is likely to be strongly influenced by the language they use to describe breathlessness and the limited vocabulary available to describe breathlessness Table 6 Relationship Between Clusters of Descriptors and Disease Groups Obtained by Mahler et al. 5 Cluster Name Descriptor Asthma n 56 COPD n 85 Interstitial Lung Disease n 37 Cardiac Failure n Rapid 1 * 2. Exhalation 2 * 3. Shallow 4 4. Work/Effort 5, 6, 10, 11 * * * * 5. Suffocating 7, 8 6. Hunger 9 7. Tight 12, 13 * 8. Heavy Inhalation 3 * 10. Breathing more 15 For key to descriptors, see Table 4.

8 Vol. 23 No. 3 March 2002 Qualitative Aspects of Breathlessness 189 Table 7 Descriptors Selected Most Frequently by Patients in Mahler et al. s Study 5 Patient Group Descriptor Asthma (n 56) I cannot get enough air. (50%) My chest feels tight. (41%) My breathing requires effort. (29%) COPD (n 85) Interstitial Lung Disease (n 37) Cardiac Failure (n 17) My breathing requires effort. (51%) I feel out of breath. (49%) I cannot get enough air. (38%) I feel out of breath. (54%) My breathing requires effort. (35%) My breathing is rapid. (30%) I cannot get enough air. (30%) My breathing requires effort. (47%) I feel out of breath. (35%) My chest feels tight. (29%) My breath does not go in all the way. (29%) My breath does not go out all the way. (29%) The number in parentheses represents the percentage of patients who selected that descriptor as one of their best three. may result in the same word being used to describe different sensations due to different mechanisms. For example, the use of my chest feels tight by patients with asthma, cardiac failure and those with cancer and pleural disease is unlikely to represent a common sensation arising from an identical mechanism. 10 There is some evidence to suggest that descriptors may be of more use in studies that examine the response to treatment or mechanisms of exercise limitation in specific groups of patients. 11,12 However, our study has not been able to find a way in which patients use of descriptors could be exploited to aid differential diagnosis, or by comparing different diagnostic groups of patients, improve our understanding of the mechanisms of breathlessness. Acknowledgments The authors would like to thank Dr. Richard Schwartzstein for his helpful comments on the manuscript; Professor Britton, Professor Carmichael, Dr. Macfarlane, Dr. Morris and Dr. Woll for allowing us access to their patients; Sister Debra Clarke for her help with the data collection; and the patients and staff at Hayward House who took part in this study. References 1. Comroe JH. Some theories on the mechanism of dyspnea. In: Howell JBL, Campbell EJM, eds. Breathlessness: proceedings of an international symposium. London: Blackwell Scientific, 1966: Simon PM, Schwartzstein RM, Weiss JW, et al. Distinguishable sensations of breathlessness induced in normal volunteers. Am Rev Respir Dis 1989;140: Simon PM, Schwartzstein RM, Weiss JW, et al. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990;142: Elliot MW, Adams L, Cockcroft A, et al. The language of breathlessness: Use of verbal descriptors by patients with cardiopulmonary disease. Am Rev Respir Dis 1991;144: Mahler DA, Harver A, Lentine T, et al. Descriptors of breathlessness in cardiorespiratory diseases. Am J Respir Crit Care Med 1996;154: Dales RE, Spitzer WO, Tousignant P, Schechter MT, Suissa S. Clinical interpretation of airway response to a bronchodilator. Epidemiological considerations. Am Rev Respir Dis 1988;138: Heyse-Moore LH. On dyspnea in advanced cancer. MD thesis. University of Southampton Skevington SM, Pilaar M, Routh D, MacLeod RD. On the language of breathlessness. Psychology and Health 1997;12: Schwartzstein RM. The language of dyspnea. In: Mahler DA, ed. Dyspnea. New York: Marcel Dekker, 1998: Manning HL, Schwartzstein RM. Pathophysiology of dyspnea. N Engl J Med 1995;333: Moy ML, Lantin ML, Harver A, Schwartzstein RM. Language of dyspnea in assessment of patients with acute asthma treated with nebulized albuterol. Am J Respir Crit Care Med 1998;158: O Donnell DE, Bertley JC, Chau LKL, Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation. Am J Respir Crit Care Med 1997;155: