Obese patients often complain of dyspnea despite

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1 Relationship of Dyspnea to Respiratory Drive and Pulmonary Function Tests in Obese Patients Before and After Weight Loss* Hesham El-Gamal, MD; Ahmad Khayat, MD; Scott Shikora, MD; and John N. Unterborn, MD Background: Dyspnea is a common complaint in obese patients, who also frequently have abnormal pulmonary function test (PFT) results without evidence of lung disease. We studied the relationship between dyspnea, PFT results, and respiratory drive in morbidly obese patients before and after weight loss. Method: Twenty-eight obese patients underwent PFTs including spirometry, lung volume measurements, and ventilatory drive assessment using the carbon dioxide rebreathing technique. The score of the dyspnea portion of the Chronic Respiratory Disease Questionnaire (CRQ) was used to assess dyspnea. CRQ and respiratory drive measurements were repeated in 10 patients after induced weight loss by gastroplasty Results: Mean SD body mass index (BMI) prior to surgery was kg/m 2. Patients were then classified into two groups: group 1, mild-to-moderate dyspnea (dyspnea score > 4); and group 2, severe dyspnea (dyspnea score < 4). Group 2 had higher respiratory drive parameters and significantly lower lung volumes compared to group 1. After gastroplasty, there were significant reductions in BMI (p 0.000), dyspnea score (p 0.000), occlusion pressure 100 ms after the start of inspiration (P 100 ) at end-tidal carbon dioxide (ETCO 2 )of60mmhg(p 0.011), minute ventilation (V E) at ETCO 2 of 60 mm Hg, and V E slope (0.017). P 100 slope was reduced, but it did not reach statistical significance. Conclusion: The degree of dyspnea commonly observed in obese patients can be explained, in part, by increased ventilatory drive and reduced static lung volumes. Gastroplasty results in a significant reduction in BMI and respiratory drive measurements as well as significant improvement in dyspnea. (CHEST 2005; 128: ) Key words: dyspnea; obesity; pulmonary function tests Abbreviations: BMI body mass index; CRQ Chronic Respiratory Disease Questionnaire; Dlco diffusion capacity of the lung for carbon monoxide; ERV expiratory reserve volume; ETCO 2 end-tidal carbon dioxide; FRC functional residual capacity; MVV maximum voluntary ventilation; P 0.1 slope of the pressure; P 100 occlusion pressure 100 ms after the start of inspiration; PFT pulmonary function test; TLC total lung capacity; V e minute ventilation; V o 2 oxygen consumption *From the Pulmonary and Critical Care Division, Departments of Medicine (Drs. El-Gamal, Khayat, and Unterborn) and Surgery (Dr. Shikora), Tufts-New England Medical Center, Boston, MA. Manuscript received February 9, 2005; revision accepted June 1, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: John N. Unterborn, MD, Pulmonary and Critical Care Division, Department of Medicine, Tufts-New England Medical Center, 750 Washington St, Boston, MA; junterborn@tufts-nemc.org Obese patients often complain of dyspnea despite not having demonstrable lung disease. 1,2 It has been hypothesized that increased chest wall mass along with increased abdominal size imparts a restrictive ventilatory defect, which then imposes an increased work of breathing. 2 Dyspnea is often attributed to this change in pulmonary physiology as well as the patient s increased weight and deconditioning. However, there is no evidence that definitively links dyspnea to the body mass index (BMI) or the percentage of ideal body weight. One study 3 correlated dyspnea in this population with maximum voluntary ventilation (MVV), which was also linked with a more pronounced lowering of static lung volume. It has been demonstrated that normocapneic obese individuals have an increased respiratory drive when compared to normal subjects. 4 Also, normal individuals who have weight placed on their chest 3870 Clinical Investigations

2 walls also exhibit an increased drive when measured by carbon dioxide rebreathing and by diaphragmatic electromyogram responses. 5 7 The severity of dyspnea has been shown to correlate with increased ventilatory drive in pregnancy, 8,9 asthma, 10 and COPD. 11 Therefore, we hypothesize that the dyspnea in obesity is related to an increased respiratory drive similar to those pulmonary disorders, and we want to establish if weight loss induced by gastroplasty has any effect on respiratory drive. We also studied if a reduction in lung volumes could also be a surrogate marker for increased respiratory load and therefore predict the severity of dyspnea. Materials and Methods Patients 18 old who were being evaluated for gastric bypass aimed at weight reduction at the New England Medical Center between March 2000 and October 2002 and who underwent routine pulmonary function tests (PFTs) as part of their preoperative screening were asked to participate in the study. The study was approved by the Human Investigation Review Committee at our institution, and all patients gave informed, written consent. Patients were excluded if they had one of the following: a history of chronic lung disease, smoking, hypoventilation syndrome, obstructive lung disease, or changes in PFT results inconsistent with changes seen in obesity (such as a FEV 1 /FVC ratio 70, or a low diffusion capacity of the lung for carbon monoxide [Dlco]). Patients were also excluded if they had a history of sleep-disordered breathing or any symptoms suggesting obstructive sleep apnea. BMI was recorded in all subjects before and after weight loss. Patients underwent PFTs as part of a routine preoperative evaluation that included spirometry, MVV, static lung volumes measured by nitrogen washout, and single-breath Dlco (Vmax229; SensorMedics; Yorba Linda, CA). Results were recorded as percentage of predicted using the European Respiratory Society 1997 regression equations. Patients enrolled in the study also underwent ventilatory drive assessment, using carbon dioxide rebreathing technique described by Read 12 using 7% carbon dioxide as initial concentration. The occlusion pressure 100 ms after the start of inspiration (P 100 ) 13,14 was measured in a random fashion with software provided with a metabolic cart (Vmax; SensorMedics). Minute ventilation (V e) was also measured using a pneumotachograph, and end-tidal carbon dioxide (ETCO 2 ) was measured directly with an infrared analyzer. The test was terminated when ETCO 2 reached 65 mm Hg or if the patient was too uncomfortable to continue. Both P 100 and V e were plotted against ETCO 2, and a best fit line was calculated using statistical software (version 9; SPSS; Chicago, IL). The slope of the line from this calculation and the ETCO 2 value of 60 mm Hg extrapolated from the line equation were then reported as the parameters of respiratory drive. Patients were also asked to take the Chronic Respiratory Disease Questionnaire (CRQ), 15 which has four domains: fatigue, mastery, dyspnea, and emotional function. The average response to the dyspnea domain questions was considered the dyspnea score. We then performed CRQ and respiratory drive measurements on a total of 10 patients 12 months after gastroplasty. All statistics were computed using statistical software (version 9; SPSS). Linear regression was performed to look for correlations between physiologic parameters and dyspnea score. Patients were also classified into two groups based on their dyspnea score (mild or no dyspnea vs moderate or severe dyspnea) for analysis. For all recorded parameters, the mean value and SEM were calculated. Means of the two groups were compared using the Student t test, and the values for the CRQ and respiratory drive before and after weight loss were compared using a paired t test. Results Originally, a total of 29 patients participated in the study, but 4 patients were excluded because they could not tolerate respiratory drive testing. The mean BMI was kg/m 2 ; Table 1 lists mean PFT results. All patients had an FEV 1 /FVC ratio 70%. All patients showed some degree of dyspnea. When using a linear regression model, dyspnea score did not correlate with BMI, weight, MVV, resting oxygen consumption (V o 2 ), and V o 2 /kg. We did find weak correlations (R 2 0.3) between expiratory reserve volume (ERV) and functional residual capacity (FRC) and the dyspnea score. Comparing those with mild dyspnea (group 1, dyspnea score 4) with those with moderate-to-severe dyspnea (group 2, dyspnea score 4), lung volumes (ERV, FRC, total lung capacity [TLC]) were significantly lower in group 2 than in group 1 (Table 2). BMI, V o 2,V o 2 /kg, and MVV did not differ significantly between the two groups. The patients in group 2 were found to have a significantly higher V e slope than group 1. However, the V e at ETCO 2 of 60 mm Hg was not significantly different between the groups. The slope of the pressure (P 0.1 ) and the P 0.1 at an ETCO 2 of 60 mm Hg were increased in group 2, but this did not reach statistical significance. After gastroplasty, 10 patients underwent repeat respiratory drive measurements and repeat CRQ; there was a significant reduction in BMI and an improvement in the dyspnea score (Table 3). All of the respiratory drive parameters were significantly reduced except for the slope of the P 100, which did not reach statistical significance. Unfortunately, the small numbers did not allow comparison between the originally defined groups. Table 1 Baseline Measurements of All Patients Parameters Mean SD BMI FVC, % predicted FEV 1, % predicted FEV 1 /FVC ratio 81 4 TLC, % predicted FRC, % predicted ERV, % predicted Residual volume, % predicted Dlco, % predicted MVV, % predicted CHEST / 128 / 6/ DECEMBER,

3 Factors Table 2 Comparison Between the Two Groups of Dyspneic Patients* Dyspnea Group 1, Mild to Moderate (n 12) Group 2, Severe (n 16) p Value BMI, kg/m TLC, % predicted FRC, % predicted ERV, % predicted Residual volume, % predicted MVV, % predicted P 100 plot against ETCO 2,cmH 2 O/mm Hg V e plot against ETCO 2, L/m/mm Hg P 0.1 at ETCO 2 of 60 mm Hg, cm H 2 O V e at ETCO 2 of 60 mm Hg, L/min V o 2 /kg, L/min/kg *Data are presented as mean SD. Discussion Table 3 Data on 10 Patients Retested 12 Months After Gastroplasty* Variables Before After p Value BMI, kg/m Dyspnea score P 100 at ETCO 2 of mm Hg, cm H 2 O V e at ETCO 2 of mm Hg, L/min P 100 slope, cm H 2 O/mm Hg V e slope, cm H 2 O/mm Hg *Data are presented as mean SD. Obese subjects commonly complain of dyspnea. 1,2 In our study, all of the 25 patients had at least some dyspnea as assessed by the dyspnea domain of the CRQ. 15 The severity of their shortness of breath seemed to correlate with lower static lung volumes. We also demonstrated that the sensation of dyspnea evaluated by dyspnea score is associated with higher respiratory drive parameters and that these improve with weight loss. This likely indicates that obese patients with more restriction have a higher respiratory load leading to an increased respiratory drive. The fact that the respiratory drive decreased and the dyspnea score improved significantly as the patients lost weight after gastroplasty does help to confirm this relationship. It also demonstrates that the physiologic changes that lead to the increase in drive are indeed related to the excess weight. However, it is unclear why some obese subjects who have the same BMI are affected by dyspnea more than others. It is clear from our data that BMI is not solely responsible for these changes, as we could not show a significant correlation between dyspnea, drive, or lung volumes to BMI. The possible explanations include the following: (1) the distribution of obesity, 16 (2) airway changes, 17,18 (3) abnormalities in sleep-related breathing, (4) differences in oxygen utilization by the periphery, or (5) some other parameter that improves with weight loss. 19 In terms of the distribution of obesity, it certainly is plausible that those with higher waist-to-hip ratios are more likely to have a reduction in lung volume than those with lower ratios. 16,20 In fact, in a previous study, 21 the likelihood that lung volumes will be reduced are related to the relation of height to weight, and it has been demonstrated that a load imposed on the chest wall increases drive more than one placed on the abdomen in normal volunteers. 5 Unfortunately, we did not record the waist-to-hip ratio during the study. An increase in respiratory system resistance may play a role in increasing in respiratory load and the sense of dyspnea. It has been demonstrated that respiratory system resistance is elevated in people with simple obesity and is higher with increase in BMI or presence of obesity hypoventilation syndrome. 17,22 Those changes become even more pronounced if the patient assumes a supine position. 23 An increase in upper airway resistance or mild sleep apnea may also contribute to the higher load imposed on the respiratory system. Small airway changes in obesity are well described 18 and also likely contribute to the increased load in these patients. But upper airway changes may also play a role. In a previous study, 3 patients with low MVV have been found to have lower lung volumes, and one explanation may be due to an increase in upper airway resistance. However, in contrast to previous findings, 3 our study did not show any significant correlation between dyspnea score and MVV, and the effects of upper airway resistance in obesity other than its role in obstructive sleep 3872 Clinical Investigations

4 apnea have yet to be studied. The fact that we were unable to show a correlation between MVV and dyspnea may be related to our much smaller study size compared to the previous study. 3 Another explanation for increased respiratory load and sense of dyspnea is decreased respiratory system compliance, as shown in previous studies, 22,24 although these data have been challenged in another study. 25 One weakness in our study is that we did not use polysomnography to exclude obstructive sleep apnea in these patients. Although it is likely that there was some sleep-disordered breathing in this population, we believe that this did not play a significant role, as we excluded patients from our study who had daytime hypersomnolence or any other symptoms that suggested severe obstructive sleep apnea. We also did not evaluate the blood gas levels in our patients to look for obesity hypoventilation syndrome; however, significant obesity hypoventilation syndrome also was not likely present in our patients, since all of our patients had normal baseline ETCO 2. Sleep apnea and obesity hypoventilation syndrome have also shown to decrease respiratory drive, and all the patients prior to weight loss in our study had increased respiratory drive parameters. As the next part of our investigation, we are studying if there is indeed a link between sleep apnea and dyspnea in relation to their pulmonary function and respiratory drive in these individuals. Metabolic factors may also increase respiratory load and increased dyspnea in this population. It has been demonstrated that during exercise, obese individuals have a higher V o 2 for a given work rate. 19,26,27 This likely represents a higher metabolic need secondary to the larger mass found in these patients. 22,28 We looked at baseline V o 2 adjusted for weight and found no differences between the two groups for this parameter, but we did not look at these values with exertion, which may partially explain their dyspnea. Also, if this was the main factor, we would have expected less variability in the PFT results as well as better correlation with BMI. However, body composition and fat distribution 16 (not assessed in this study) that may lead to individual differences in metabolic parameters could explain the variability of dyspnea sensation in these patients. In future study, separation of total body lean body mass, body fat, and body water content by measurement of bioimpedance or orthopometric analysis would be data that would help sort out whether changes in body composition were responsible for the variability in the response to weight loss. Another weakness of our study is the lack of repeat pulmonary function data after weight loss to confirm an improvement in lung volumes. However, previous data exist that pulmonary function does indeed improve after induced weight loss We have no reason to think our population differed from that in those prior studies ; therefore, we assume that the lung volumes did return to normal or at least improved as would be predicted. The sensation of dyspnea is a subjective one and has many potential causes. By our study, it appears that the reduction in static lung volumes appear to be associated with an increased respiratory drive and subjective complaints of dyspnea. Further investigation is needed to determine how the factors of waist-to-hip ratio, airway and respiratory system resistance, respiratory muscle weakness, body composition, oxygen utilization, and sleep apnea influence the perception of dyspnea in this population. If the major cause of dyspnea can be identified, it may provide treatments that improve quality of life even before the patients are able to lose weight. Summary We found that obese patients with reduced lung volume compared to those with preserved lung volume had more dyspnea and higher respiratory drive parameters. We also demonstrated that the respiratory drive parameters and dyspnea improve greatly after weight loss, indicating that they have a role in determining the shortness of breath commonly seen in this population. ACKNOWLEDGMENT: Special thanks to the staff in the pulmonary function laboratory at the New England Medical Center in Boston: Cindy Jacoby, Stephanie Shinds, and Robyn Weiser. References 1 Burki NK. 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