Impact of obesity on respiratory functionresp_2096

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1 INVITED REVIEW SERIES: OBESITY AND RESPIRATORY DISORDERS SERIES EDITOR: AMANDA J PIPER Impact of obesity on respiratory functionresp_2096 STEPHEN W. LITTLETON Pulmonary, Critical Care, and Sleep Medicine, Cook County Hospital and Rush University Medical Center, Chicago, Illinois, USA ABSTRACT Obesity has long been recognized as having significant effects on respiratory function. The topic has been studied for at least the last half century, and some clear patterns have emerged. Obese patients tend to have higher respiratory rates and lower tidal volumes. Total respiratory system compliance is reduced for a variety of reasons, which will be discussed. Lung volumes tend to be decreased, especially expiratory reserve volume. Spirometry, gas exchange and airway resistance all tend to be relatively well preserved when adjusted for lung volumes. Patients may be mildly hypoxaemic, possibly due to ventilation perfusion mismatching at the base of the lungs, where microatelectasis is likely to occur. Weight loss leads to a reversal of these changes. For all of these changes, the distribution of fat, that is, upper versus lower body, may be more important than body mass index. Key words: lung volume, obesity, pulmonary function test, pulmonary gas exchange, respiratory mechanics. INTRODUCTION The association between obesity and respiratory dysfunction is almost as old as recorded history. Dionysius, a tyrant of Heraclea, was born in approximately 360 BC. He was described as being very obese, and through daily gluttony and intemperance, increased to an extraordinary degree of Corpulency and Fatness, The Authors: Dr Littleton is an attending physician in the division of Pulmonary, Critical Care, and Sleep Medicine at Cook County Hospital in Chicago, and an assistant professor of medicine at Rush University Medical Center. His research interests include the pathophysiology of respiratory failure and hypercapnia. Correspondence: Stephen W. Littleton, Pulmonary, Critical Care, and Sleep Medicine, Attending Physician, Cook County Hospital, Rush University Medical Center, 1900 West Polk Street, Room 1416, Chicago, IL 60612, USA. slittleton@ cookcountyhhs.org Received 15 August 2011; invited to revise: 24 August 2011; revised 29 August 2011; accepted 3 September by reason whereof he had much adoe to take breath. It was also written of him that he was choked by his own fat. 1 Dionysius was not unique in ancient Greek times. Magas, the King of Cyrene, who died in approximately 258 BC, was weighted down with monstrous masses of flesh in his last days; in fact he choked himself to death. 1 There have been similar descriptions of obesity in more recent times as well. In 1816, William Wadd, whose title was Surgeon Extraordinary to the King, published a treatise in which he noted, accumulation offat...cannot fail to impede the free exercise of the animal functions. Respiration is performed imperfectly, or with difficulty. In the appendix, he mentioned three patients who had been suffocated by fat. 1 But, specifically, what are the imperfections in the respiration of obese patients? BREATHING PATTERNS OF OBESE PATIENTS Patients who are morbidly obese (BMI 40 kg/m 2 ) have increased respiratory rates as compared with normal subjects. In four studies, the mean respiratory rate of obese subjects ranged from 15.3 to 21 breaths per minute, while that of normal subjects ranged from 10 to 12 breaths per minute. 2 5 Tidal volume tends to be significantly lower in obese subjects, 3 5 although this finding is not universal. 2 Despite the decrease in tidal volume, the increase in respiratory rate is such that minute ventilation is significantly increased, and was shown to be 11 L/min or greater in most studies. 2,4,5 How does the obese patient achieve this higher respiratory rate? Is there a change in breath timing, or is the flow rate higher? It seems that there is a change in breath timing, but reports on exactly what those changes are have been inconsistent. Sampson showed that there was a decrease in inspiratory time [T I], without a significant decrease in expiratory time [T E] and no change in mean inspiratory flow. 3 In contrast, both Burki and Baker, and Chlif et al. showed that T E decreased without any change in T I or doi: /j x

2 44 SW Littleton inspiratory flow rates (as well as similar expiratory flow rates). 2,5 Finally, Pankow showed that T I and T E were decreased but did not report the statistics on flow rates. 4 Decreases in T I may arise from increased activity of chest-wall receptors or from changes in central breath timing, 3 whereas decreases in T E could be due to an increased expiratory flow rate as a result of decreased total respiratory compliance, 2 or persistent diaphragmatic activity extending into exhalation. 3 It seems that both T I and T E are affected by obesity, although the exact pattern of changes may vary among individuals. RESPIRATORY MECHANICS Total respiratory system compliance is undoubtedly reduced in obese patients However, the results are contradictory as to whether this reduced compliance is due to reduced chest-wall compliance, lung compliance or some combination of the two. In 1960, Naimark and Cherniack showed that chestwall compliance was reduced in obese individuals (and was especially reduced in the supine position), whereas lung compliance was normal. 7 Four years later, Sharp et al. showed nearly the exact opposite: chest-wall compliance was normal, and that a decrease in lung compliance was largely responsible. 8 Using a non-invasive method, Suratt et al. showed the chest wall of obese patients to be normal while they were seated. 11 Oesophageal pressures, and therefore calculations of lung and chest compliance, changed between the seated and the supine positions. 7,12 These studies were performed on awake patients, in whom respiratory muscle activity may have interfered with the measurements. When Hedenstierna and Santesson performed similar studies on paralyzed, supine subjects, chestwall compliance was found to be normal and lung compliance was reduced. 9 Pelosi et al. studied nearly equally obese patients under the same conditions, and found that both chest and lung compliance were reduced. 10 It is likely that both decreased lung compliance and decreased chest-wall compliance contribute to a less compliant respiratory system in obese patients. Decreased lung compliance is likely to be the result of decreased lung volumes, leading to microatelectasis, which shifts normal respirations into the sinusoidal rather than the linear portion of the pressure-volume curve. 9,10 Chest-wall compliance may be dependent on the pattern of fat distribution in a particular patient. It is known that mass loading of the lower thorax and upper abdomen of supine, paralyzed subjects affects chest-wall compliance more so than mass loading of the upper thorax. 13 Therefore, chest-wall compliance may be more relevant in patients with higher waist-to-hip ratios. LUNG VOLUMES The effects of obesity on lung volumes have been studied extensively. Figure 1 summarizes the effects Figure 1 Summary of the effect of obesity on lung volumes. Expiratory reserve volume (ERV) is decreased in obesity. Functional residual capacity (the sum of ERV and residual volume) is usually decreased as well, but to a lesser extent, since RV is usually relatively well preserved. Tidal volume is usually reduced, but not to the extent that it is apparent in this schematic. Total lung capacity can be slightly reduced or normal. From: Sood A. Altered resting and exercise respiratory physiology in obesity. Clin. Chest Med. 2009; 30: , Inspiratory Reserve Volume;, Tidal Volume;, Expiratory Reserve Volume;, Residual Volume. of obesity on lung volumes. One of the most consistent effects of obesity on lung volumes is a decrease in expiratory reserve volume (ERV) ERV decreases as BMI increases. 14,17,19,22,23 One study of pulmonary function tests in 373 patients with a wide range of BMI showed that those with mild obesity (BMI kg/ m 2 ) had an ERV of only % of predicted. That study also showed that ERV decayed exponentially with increasing BMI (Fig. 2). 17 Another study showed that super obese individuals (BMI 60 kg/m 2, or a height/weight ratio of 1) had an ERV of only % of predicted. 19 An equally consistent negative correlation between obesity and FRC can be demonstrated, although the changes are less dramatic. 14,17,23,24 Individuals with a BMI >40 kg/m 2 have an FRC of % of predicted. If there is an exponential relationship between BMI and ERV, then the same should hold true of FRC, and this was shown to be the case. Given that there is a significant but very modest effect of BMI on RV, then the reduction in FRC is due to the reduction in ERV. 17 If obesity reduces ERV and FRC, then we might expect a similar effect on TLC. In reality, TLC is not affected unless patients are massively obese. Older studies with limited numbers of patients showed a significant difference, only when normal subjects were compared with those with a height to weight ratio of (BMI of 55 kg/m 2 for a person 183 cm tall, and greater if the person is shorter), 22 or if the cohort had a mean body weight of % of the ideal (BMI of approximately 46.6 kg/m 2 ). 2 A small but more recent study did not find a significant difference in TLC when two groups with mean BMIs of 25.5 and 38.8 were compared. 25 However, when the BMI of the obese group was 47, whereas that of the normal group remained at 25, a significant difference emerged. 21

3 Impact of obesity on respiratory function 45 Figure 2 Exponential relationship between expiratory reserve volume (ERV) and BMI. Note that ERV falls below the range of normal (<80% predicted) at a BMI of 25 kg/ m 2, which is considered merely overweight. The r 2 value for ERV is 0.49 (P < ). From Jones R, Nzekwu M. The effects of body mass index on lung volumes. Chest 2006; 130: Significant but probably clinically unimportant differences did emerge when larger groups of patients were studied. One study found that the TLC of a group of subjects with a mean BMI of 34 was 15% below predicted when compared with that of a group with a mean BMI of In another study, there was a 0.5% decrease in predicted TLC for each unit increase in BMI, although mean TLC in the group with BMI 40 was only 12% below predicted, on average. 17 How does obesity have these effects on lung volumes? One proposed mechanism is that abdominal fat displaces the diaphragm into the abdomen. 26 This is supported by one study that showed lung volumes were affected more in patients with a waistto-hip ratio >0.95 ( upper body fat distribution). 27 In addition, chest-wall adiposity may simply compress the thoracic cage, leading to lower lung volumes. 26 This is supported by the similar pattern observed when lung volumes are measured after elastic strapping of the chest, 28 although there is some question as to whether obesity acts as a mass (threshold) load or an elastic load. 13 It is likely that both play a role in decreasing lung volumes, and it would be difficult to isolate and study one component independently. Recently, MRI has become the preferred method for localizing and quantifying adiposity. 29 No studies have been done yet on whether abdominal adiposity as determined by MRI is correlated with reduced lung volumes, but a recent preliminary study explored a third possible mechanism for the effect of obesity on lung volumes: is there an increase in thoracic or mediastinal fat in obese patients? Normal weight subjects (BMI 25.0) were compared with obese subjects (BMI 38.8). The obese subjects were then divided into two groups: those with a TLC <80% of predicted (obese restricted) and those with a TLC >80% of predicted (obese normal). Although obese subjects did have more mediastinal fat than normal subjects, there was no difference in mediastinal fat between the obese restricted and the obese normal subjects. In fact, the only discernible difference between the two obese groups was the intrathoracic volume at full breath hold; 124% of predicted TLC in the obese normal group, and 105% of predicted TLC in the obese restricted group. The authors hypothesized that a reduction in diaphragmatic excursion due to abdominal fat was responsible. 25 Another recent study used MRI to compare endexpiratory lung volume and fat distribution in obese men and women (BMI of 35 4 and 37 2, respectively) with that in normal subjects. Surprisingly, that study showed little variation in the distribution of fat between normal subjects and obese subjects, for both men and women. This underscores the difficulty of teasing out the relative contributions of chest wall and abdominal fat to alterations in lung volumes. The study did show a significant relationship between visceral fat, that is, fat surrounding the abdominal organs, anterior subcutaneous fat (both abdominal and chest wall) and end-expiratory lung volume (expressed as % TLC). 30 The study also highlighted the fact that both chest wall and abdominal fat likely play a role in derangement of lung volume. Further research on the quantification of abdominal fat by MRI is likely to be forthcoming and will be very helpful in elucidating the exact mechanisms that are at work. SPIROMETRY Obesity generally does not depress FEV 1 or FVC unless patients are massively obese. The FEV 1/FVC ratio is preserved. 2,17,19 21,24,25,27,31 33 Figure 3 shows the typical spirogram of an obese patient. One large study showed a statistically significant trend in men and a nearly significant correlation in women, between FEV 1, FVC and BMI, although FEV 1 in men with a mean BMI of 33.6 was close to normal at 93% of predicted. 32 Even in massively obese individuals, the effects are modest. One study showed that the mean FEV 1 in 18 patients with weight to height ratios >1 was % of predicted. 19 These effects disappeared when FEV 1 and FVC were adjusted for the small reduction in lung volumes. Again, it seems that the pattern of obesity is more significant than BMI alone. Abdominal obesity is generally correlated with reductions in FEV 1 and FVC, with some exceptions being noted for women and certain age groups, depending on the study. 27,31,32,34 The largest study involved almost subjects and showed an inverse linear correlation between

4 46 SW Littleton midtidal lung volume did not account for the increase in total respiratory resistance measured at the mouth. 24 The reasons for the inconsistency in these findings, especially the differences between the genders, are unclear. Airway remodelling secondary to inflammatory adipokines, or even direct lipid deposition in the airways are two possible explanations. 37 Given the differences between the genders, some hormonal interplay may also be involved. OXYGENATION, VENTILATION, PERFUSION AND GAS EXCHANGE Figure 3 Flow-volume loops from a healthy obese female, aged 35, BMI 43 kg/m 2, with reduced TLC, FRC and VC, but well-preserved expiratory follows. The dashed line shows the predicted flow-volume loop, and the solid line the actual loop. The predicted lung volumes are shown on the bar, the vertical arrow shows predicted flow at 50% capacity, and the horizontal arrow shows the actual volume. From: Salome CM, King GG, Berend N. Physiology of obesity and effects on lung function. J. Appl. Physiol. 2010; 108: waist-to-hip ratio and FEV 1 and FVC. 34 Other measurements of abdominal obesity that have shown associations with spirometric parameters are biceps 27 and subscapular skin fold thickness, 31 waist circumference 35 and abdominal height. 32 AIRWAY RESISTANCE Airway resistance is usually increased in obese individuals, and this is at least partly related to the lower lung volumes at which obese patients normally breathe, leading to closure of the smaller airways. 20,21,24 One case-controlled study of 190 subjects showed that the airway resistance of obese men (mean BMI 47) was almost twice that of normal control subjects. Interestingly, although the differences in airway resistance between normal-weight and obese women were significant, they were much less profound. However, when airway conductance (the inverse of airway resistance) was adjusted for lung volumes, there was no difference between the normal subjects and the obese subjects. 21 Another study showed a very strong correlation between % predicted FRC and airway conductance, but not between conductance and BMI. Direct measurements confirmed that airway calibre and BMI were correlated in men, but only weakly correlated in women. However, the same study showed that the decrease in lung volumes only accounted for a portion of the increase in airway resistance. 36 Similarly, another study showed that the decrease in 8,38 40 Obese patients may have a normal,, or slightly reduced PaO 2. 16,19 The reasons for the differences in the results of these studies are unclear, but may be related to obesity-hypoventilation syndrome, since one study showed a mean PaCO 2 of mm Hg. 19 One study of 37 massively obese patients (BMI of approximately 50) showed a relatively normal mean PaO 2 of mm Hg, 38 whereas another study of 25 patients with a mean BMI of 49.0 showed a nearly identical mean PaO 2 of 88 7mmHg. 40 It is not clear whether simple obesity, in and of itself, is sufficient to cause arterial hypoxaemia. It does seem, however, that obesity causes a mild widening of the A-aO 2 gradient. In the two previously mentioned studies, the subjects with BMIs of were free of pulmonary disease and had A-aO 2 gradients of and 19 9mmHg, 40 respectively. Therefore, although obesity can cause a mild widening of the A-aO 2 gradient, this is not sufficient to cause frank hypoxaemia. The widening of the A-aO 2 gradient is likely caused by ventilation perfusion mismatch. The lung bases are relatively overperfused and underventilated when obese patients are studied in the sitting position, 41 and when they are recumbent. 42 This is due to the closure of small airways in dependent lung zones. 43 This would cause the pattern discussed earlier; that is, a reduction in ERV with a relatively unchanged RV. Furthermore, there is also a correlation between ERV and both hypoxaemia and A-aO 2 gradient. In one study, V/Q was much more closely matched in four obese subjects with an ERV of 49% of predicted than in four subjects with an ERV of 21% of predicted. These latter subjects had identical perfusion to the lower lung zones, but a much higher proportion of ventilation to the upper lung zones. 41 Another study showed a linear relationship between PaO 2 and absolute ERV, and many of these patients had a closing volume in excess of ERV. 39 Once again, there is a significant relationship between the pattern of obesity and pulmonary function. Recent work has shown a significant linear relationship between waist-to-hip ratio and PaO 2, PaCO 2 and A-aO 2 gradient. 40 Gas exchange (DL CO) seems to be relatively well preserved in subjects with simple obesity. 8,19,22,44,45 When corrected for lung volume (DL CO/V A), values may be elevated in extremely obese (height/weight ratio

5 Impact of obesity on respiratory function 47 >1.10) compared with normal-weight individuals, 22 although this finding has not been consistently reported. 19 One study in which factors that were correlated with an increased DL CO/V A were examined retrospectively showed that a reduction in VC was a common finding, and that obesity was a common cause of this reduction. 46 DL CO/V A may be increased in obese patients due to an increase in pulmonary blood volume 8,46 EXERCISE Since obese individuals have a higher basal metabolic rate (VO 2) than lean subjects, it is not surprising that they have a higher oxygen consumption during exercise for any given work rate. 44,45,47,48 The slopes of the VO 2 to work rate lines are the same as in normalweight individuals, implying that it is the increase in basal rate that is responsible for the increase in VO 2 at a given work rate, although this may also result from the extra energy needed to move heavier legs during cycling exercise protocols. 49 Obese patients also tend to have a lower anabolic threshold. 50 The A-aO 2 gradient, and PaO 2 if it is abnormal, actually improve during exercise. 49 Augmented tidal volumes help to open the closed, dependent lung units, which are thought to be the primary cause of the increased A-aO 2 gradient. 51 In addition to having a lower A-aO 2 gradient, obese patients augment their oxygen intake by increasing their tidal volumes and respiratory rates during exercise, similar to normal weight subjects. However, as they burn more oxygen, they need to augment their minute ventilation to an even greater extent than normal-weight subjects. This is achieved mainly through a higher respiratory rate, as their tidal volumes are not generally greater. 44,48,50 The reason why is unclear. It may be simply due to central breath timing, but again, we see some evidence that it could be related to body fat distribution leading to impaired diaphragmatic excursion, and therefore an inability to augment exercise tidal volumes any further. In one large, relatively recent study, 164 morbidly obese females (BMI kg/m 2 ) were divided into two groups: those with an upper body distribution of fat (waist-hip circumference ratio 0.80) and those with a lower body distribution of fat. All subjects were exercised to the point of maximum effort. Those with an upper body distribution of fat had a significantly lower anaerobic threshold, and a significantly higher VO 2 max. In addition, the group with upper body fat had a significantly higher respiratory rate and minute ventilation at both anaerobic threshold and maximal exercise, whereas tidal volume did not differ significantly. Maximal exercise workload was equivalent in the two groups. 50 The results from this study imply that the group with upper body fat was simply unable to augment their tidal volume as much as the group with lower body fat, and the increase in minute ventilation was insufficient to meet metabolic needs. The higher oxygen consumption in the group with upper body fat may have been due to a higher oxygen cost of work of breathing (see below). Further studies using MRI quantification and determination of fat distribution are necessary to confirm these interesting findings. DYSPNOEA Obesity has long been thought to be a cause of dyspnoea, especially on exertion, but data supporting this have been scarce. A relatively recent, large study involving participants showed that obesity was a risk factor for self-reported dyspnoea. Individuals in the highest quintile of BMI (>31.0 kg/m 2 ) had an odds ratio of 2.66 (95% CI , P = 0.001) for reporting dyspnoea when walking up a hill, as compared with those in the control quintile (BMI kg/m 2 ). Individuals in the highest quintile of BMI were also more likely to self-report asthma or to have used a bronchodilator in the last month, but were the least likely to actually have airflow obstruction (8.7%, compared with 12.8% of those in the control quintile, P = 0.001). 52 This highlights the frequency of misdiagnosis among these patients. What are the origins of obesity-related dyspnoea? The data in this regard are inconclusive, and given the complex mechanisms underlying dyspnoea, 53 the cause is likely to be multifactorial. Many potential causes have been investigated. In one study, 28 obese patients were divided into two groups: those with mild to moderate dyspnoea and those with severe dyspnoea. Although BMI did not differ significantly between the groups ( and kg/m 2, respectively) the group with severe dyspnoea had significantly lower TLC, FRC and ERV values, and tended to have a higher respiratory drive. 54 Other studies have shown that dyspnoea in obese subjects is related to respiratory muscle performance 23,55 or rib cage muscle activity, 56 afferent feedback from which is known to contribute to the sensation of dyspnoea. 53 Further supporting the idea that increased respiratory muscle work leads to dyspnoea in these patients is the observation that they also have an increased oxygen cost of breathing. It is already known that obese patients have a higher oxygen cost of breathing, even at rest. 57 In a recent study, two groups of obese women, eight with exertional dyspnoea (BMI 37 4 kg/m 2 ) and eight without (BMI 36 5 kg/m 2 ), were investigated. They were exercised at a constant work rate and also underwent a eucapnic voluntary hyperpnoea manoeuvre. Their perceptions of breathlessness, as well as the oxygen cost of breathing were measured during both experiments. There were no differences between the groups with respect to pulmonary function tests or respiratory mechanics. But, there was a strong, statistically significant relationship between oxygen cost of breathing and perceived breathlessness (Fig. 4). Very interestingly, there were no differences in peak cardiovascular exercise capacity or fat distribution as determined by MRI, between the groups. 58 It remains unclear why certain obese individuals have a higher oxygen cost of breathing compared with others, equally obese persons.

6 48 SW Littleton obese patients experience dyspnoea, whereas others do not. CONCLUSION Figure 4 Relationship between oxygen cost of breathing and rating of perceived breathlessness (RPB) in obese women with (n = 7) or without (n = 7) exertional dyspnoea during a voluntary eucapnic hyperpnoea protocol. Reprinted with permission of the American Thoracic Society. Copyright American Thoracic Society. From: TG Babb, KG Ranasinghe, LA Comeau, TL Semon, B Schwartz; 2008; Dyspnea on exertion in obese women ; American Journal of Respiratory and Critical Care Medicine; Volume 178, pp Official Journal of the American Thoracic Society., Obese with Dyspnea;, Obese without Dyspnea. EFFECTS OF WEIGHT LOSS ON PULMONARY FUNCTION Perhaps one of the best ways of studying the effects of obesity on pulmonary function is to study the same group of patients before and after weight loss, each patient acting as their own control. It seems that most of the changes associated with obesity are reversed after significant weight loss, and are therefore likely to be caused by obesity itself. ERV, the pulmonary parameter that is most consistently altered in obesity, improves after weight loss. 16,18,33,38,39,54,59,60 One study showed a tripling of absolute ERV in patients whose mean BMI decreased from 45 to 39 kg/m 2 after a very low calorie diet. 60 Even modest weight loss (reduction in BMI from 35 to 33 kg/m 2 ) leads to modest but significant improvements in ERV. 33 FRC and TLC also improve to varying degrees. 16,18,38,59,60 The A-aO 2 gradient also tends to improve if DBMI is >20 kg/m 2 after jejunoileal bypass. The DA-aO 2 gradient is linearly correlated with DBMI. 39 This supports the hypothesis that a widened A-aO 2 gradient in obesity is caused by closure of some lung units from a closing volume that is above ERV, with resultant V/Q mismatch. Respiratory muscle endurance also improves, 59 although maximum voluntary ventilation does not. 54 A reduction in BMI from to as a result of gastric bypass led to a decrease in respiratory drive and decreased dyspnoea in 10 patients. 54 Further study of this topic could help explain why some Obesity has myriad effects on pulmonary function. Respiratory rate is usually increased in order to compensate for the normally depressed tidal volumes. Total respiratory system compliance is decreased; however, partitioning this into chest wall and lung components has shown conflicting results. Lung volumes, and especially ERV, are the most consistently affected respiratory parameters. Oxygenation may be affected, probably as a consequence of microatelectasis at the lung bases. In individual patients, the distribution of fat may be more important than BMI. Notable omissions from this review are the effects of obesity on respiratory muscle function, respiratory drive and upper airway collapsibility; these topics will be addressed in other reviews in this series. Further research on the distribution of fat and its effects may help to elucidate the still elusive concepts of dyspnoea, central breath timing and chest-wall mechanics in obese individuals. REFERENCES 1 Kryger MH. Sleep apnea. From the needles of Dionysius to continuous positive airway pressure. Arch. Intern. Med. 1983; 143: Burki NK, Baker RW. Ventilatory regulation in eucapnic morbid obesity. Am. Rev. Respir. Dis. 1984; 129: Sampson MG, Grassino AE. Load compensation in obese patients during quiet tidal breathing. J. Appl. Physiol. 1983; 55: Pankow W, Podszus T, Gutheil T et al. Expiratory flow limitation and intrinsic positive end-expiratory pressure in obesity. J. Appl. Physiol. 1998; 85: Chlif M, Keochkerian D, Choquet D et al. Effects of obesity on breathing pattern, ventilatory neural drive and mechanics. Respir. Physiol. Neurobiol. 2009; 168: Lourenço RV. Diaphragm activity in obesity. J. Clin. Invest. 1969; 48: Naimark A, Cherniack RM. Compliance of the respiratory system and its components in health and obesity. J. Appl. Physiol. 1960; 15: Sharp JT, Henry JP, Sweany SK et al. The total work of breathing in normal and obese men. J. Clin. Invest. 1964; 43: Hedenstierna G, Santesson J. Breathing mechanics, dead space and gas exchange in the extremely obese, breathing spontaneously and during anaesthesia with intermittent positive pressure ventilation. Acta Anaesthesiol. Scand. 1976; 20: Pelosi P, Croci M, Ravagnan I et al. Total respiratory system, lung, and chest wall mechanics in sedated-paralyzed postoperative morbidly obese patients. Chest 1996; 109: Suratt PM, Wilhoit SC, Hsiao HS et al. Compliance of chest wall in obese subjects. J. Appl. Physiol. 1984; 57: Mead J, Gaensler EA. Esophageal and pleural pressures in man, upright and supine. J. Appl. Physiol. 1959; 14: Sharp JT, Henry JP, Sweany SK et al. Effects of mass loading the respiratory system in man. J. Appl. Physiol. 1964; 19: Ladosky W, Botelho MA, Albuquerque JP Jr. Chest mechanics in morbidly obese non-hypoventilated patients. Respir. Med. 2001; 95: Kelly TM, Jensen RL, Elliott CG et al. Maximum respiratory pressures in morbidly obese subjects. Respiration 1988; 54: 73 7.

7 Impact of obesity on respiratory function Thomas PS, Cowen ER, Hulands G et al. Respiratory function in the morbidly obese before and after weight loss. Thorax 1989; 44: Jones RL, Nzekwu MM. The effects of body mass index on lung volumes. Chest 2006; 130: Emirgil C, Sobol BJ. The effects of weight reduction on pulmonary function and the sensitivity of the respiratory center in obesity. Am. Rev. Respir. Dis. 1973; 108: Biring MS, Lewis MI, Liu JT et al. Pulmonary physiologic changes of morbid obesity. Am. J. Med. Sci. 1999; 318: Zerah F, Harf A, Perlemuter L et al. Effects of obesity on respiratory resistance. Chest 1993; 103: Rubinstein I, Zamel N, DuBarry L et al. Airflow limitation in morbidly obese, nonsmoking men. Ann. Intern. Med. 1990; 112: Ray CS, Sue DY, Bray G et al. Effects of obesity on respiratory function. Am. Rev. Respir. Dis. 1983; 128: Collet F, Mallart A, Bervar JF et al. Physiologic correlates of dyspnea in patients with morbid obesity. Int. J. Obes. (Lond.) 2007; 31: Watson RA, Pride NB. Postural changes in lung volumes and respiratory resistance in subjects with obesity. J. Appl. Physiol. 2005; 98: Watson RA, Pride NB, Thomas EL et al. Reduction of total lung capacity in obese men: comparison of total intrathoracic and gas volumes. J. Appl. Physiol. 2010; 108: Koenig SM. Pulmonary complications of obesity. Am. J. Med. Sci. 2001; 321: Collins LC, Hoberty PD, Walker JF et al. The effect of body fat distribution on pulmonary function tests. Chest 1995; 107: Caro CG, Butler J, Dubois AB. Some effects of restriction of chest cage expansion on pulmonary function in man: an experimental study. J. Clin. Invest. 1960; 39: Heymsfield SB. Development of imaging methods to assess adiposity and metabolism. Int. J. Obes. (Lond.) 2008; 32(Suppl. 7): S Babb TG, Wyrick BL, DeLorey DS et al. Fat distribution and endexpiratory lung volume in lean and obese men and women. Chest 2008; 134: Lazarus R, Sparrow D, Weiss ST. Effects of obesity and fat distribution on ventilatory function: the normative aging study. Chest 1997; 111: Ochs-Balcom HM, Grant BJB, Muti P et al. Pulmonary function and abdominal adiposity in the general population. Chest 2006; 129: Babb TG, Wyrick BL, Chase PJ et al. Weight loss via diet and exercise improves exercise breathing mechanics in obese men. Chest 2011; 140: Canoy D, Luben R, Welch A et al. Abdominal obesity and respiratory function in men and women in the EPIC-Norfolk Study, United Kingdom. Am. J. Epidemiol. 2004; 159: Chen Y, Rennie D, Cormier YF et al. Waist circumference is associated with pulmonary function in normal-weight, overweight, and obese subjects. Am. J. Clin. Nutr. 2007; 85: King GG, Brown NJ, Diba C et al. The effects of body weight on airway calibre. Eur. Respir. J. 2005; 25: Salome CM, King GG, Berend N. Physiology of obesity and effects on lung function. J. Appl. Physiol. 2010; 108: Vaughan RW, Cork RC, Hollander D. The effect of massive weight loss on arterial oxygenation and pulmonary function tests. Anesthesiology 1981; 54: Farebrother MJ, McHardy GJ, Munro JF. Relation between pulmonary gas exchange and closing volume before and after substantial weight loss in obese subjects. Br. Med. J. 1974; 3: Zavorsky GS, Murias JM, Kim DJ et al. Waist-to-hip ratio is associated with pulmonary gas exchange in the morbidly obese. Chest 2007; 131: Holley HS, Milic-Emili J, Becklake MR et al. Regional distribution of pulmonary ventilation and perfusion in obesity. J. Clin. Invest. 1967; 46: Hurewitz AN, Susskind H, Harold WH. Obesity alters regional ventilation in lateral decubitus position. J. Appl. Physiol. 1985; 59: Douglas FG, Chong PY. Influence of obesity on peripheral airways patency. J. Appl. Physiol. 1972; 33: Dempsey JA, Reddan W, Rankin J et al. Alveolar-arterial gas exchange during muscular work in obesity. J. Appl. Physiol. 1966; 21: Salvadori A, Fanari P, Mazza P et al. Breathing pattern during and after maximal exercise testing in young untrained subjects and in obese patients. Respiration 1993; 60: Baylor P, Goebel P. Clinical correlates of an elevated diffusing capacity for carbon monoxide corrected for alveolar volume. Am. J. Med. Sci. 1996; 311: Salvadori A, Fanari P, Mazza P et al. Work capacity and cardiopulmonary adaptation of the obese subject during exercise testing. Chest 1992; 101: Babb TG, Korzick D, Meador M et al. Ventilatory response of moderately obese women to submaximal exercise. Int. J. Obes. 1991; 15: Whipp BJ, Davis JA. The ventilatory stress of exercise in obesity. Am. Rev. Respir. Dis. 1984; 129: S Li J, Li S, Feuers RJ et al. Influence of body fat distribution on oxygen uptake and pulmonary performance in morbidly obese females during exercise. Respirology 2001; 6: Sood A. Altered resting and exercise respiratory physiology in obesity. Clin. Chest Med. 2009; 30: , vii. 52 Sin DD, Jones RL, Man SFP. Obesity is a risk factor for dyspnea but not for airflow obstruction. Arch. Intern. Med. 2002; 162: Stulbarg M, Adams L. Dyspnea. In: Mason RJ, Murray JF, Broaddus VC et al. (eds) Murray and Nadel s Textbook of Respiratory Medicine. Elsevier Science Health Science div, Philadelphia, PA, 2005; El-Gamal H, Khayat A, Shikora S et al. Relationship of dyspnea to respiratory drive and pulmonary function tests in obese patients before and after weight loss. Chest 2005; 128: Sahebjami H. Dyspnea in obese healthy men. Chest 1998; 114: Lotti P, Gigliotti F, Tesi F et al. Respiratory muscles and dyspnea in obese nonsmoking subjects. Lung 2005; 183: Kress JP, Pohlman AS, Alverdy J et al. The impact of morbid obesity on oxygen cost of breathing (VO(2RESP)) at rest. Am. J. Respir. Crit. Care Med. 1999; 160: Babb TG, Ranasinghe KG, Comeau LA et al. Dyspnea on exertion in obese women: association with an increased oxygen cost of breathing. Am. J. Respir. Crit. Care Med. 2008; 178: Weiner P, Waizman J, Weiner M et al. Influence of excessive weight loss after gastroplasty for morbid obesity on respiratory muscle performance. Thorax 1998; 53: Hakala K, Mustajoki P, Aittomäki J et al. Effect of weight loss and body position on pulmonary function and gas exchange abnormalities in morbid obesity. Int. J. Obes. Relat. Metab. Disord. 1995; 19: