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.
SERIES EDITOR: AMANDA J PIPER
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. Email: email@example.com
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.
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, 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 of fat . . . 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/m2) 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 [TI], without a significant decrease in expiratory time [TE] and no change in mean inspiratory flow.3 In contrast, both Burki and Baker, and Chlif et al. showed that TE decreased without any change in TI or inspiratory flow rates (as well as similar expiratory flow rates).2,5 Finally, Pankow showed that TI and TE were decreased but did not report the statistics on flow rates.4 Decreases in TI may arise from increased activity of chest-wall receptors or from changes in central breath timing,3 whereas decreases in TE 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 TI and TE are affected by obesity, although the exact pattern of changes may vary among individuals.
Total respiratory system compliance is undoubtedly reduced in obese patients.6–10 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 chest-wall 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, chest-wall 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.
The effects of obesity on lung volumes have been studied extensively. Figure 1 summarizes the effects of obesity on lung volumes. One of the most consistent effects of obesity on lung volumes is a decrease in expiratory reserve volume (ERV).14–21 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 30–35 kg/m2) had an ERV of only 42.4 ± 29.3% 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/m2, or a height/weight ratio of 1) had an ERV of only 17.8 ± 9.6% 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/m2 have an FRC of 66.6 ± 12.3% 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 1.1–1.2 (BMI of 55 kg/m2 for a person 183 cm tall, and greater if the person is shorter),22 or if the cohort had a mean body weight of 234 ± 39.6% of the ideal (BMI of approximately 46.6 kg/m2).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 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 27.20 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 waist-to-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 end-expiratory 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.
Obesity generally does not depress FEV1 or FVC unless patients are massively obese. The FEV1/FVC ratio is preserved.2,17,19–21,24,25,27,31–33Figure 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 FEV1, FVC and BMI, although FEV1 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 FEV1 in 18 patients with weight to height ratios >1 was 68.7 ± 5.9% of predicted.19 These effects disappeared when FEV1 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 FEV1 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 20 000 subjects and showed an inverse linear correlation between waist-to-hip ratio and FEV1 and FVC.34 Other measurements of abdominal obesity that have shown associations with spirometric parameters are biceps27 and subscapular skin fold thickness,31 waist circumference35 and abdominal height.32
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 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
Obese patients may have a normal,,8,38–40 or slightly reduced PaO2.16,19 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 PaCO2 of 46.7 ± 2.5 mm Hg.19 One study of 37 massively obese patients (BMI of approximately 50) showed a relatively normal mean PaO2 of 83.2 ± 2.5 mm Hg,38 whereas another study of 25 patients with a mean BMI of 49.0 showed a nearly identical mean PaO2 of 88 ± 7 mm Hg.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-aO2 gradient. In the two previously mentioned studies, the subjects with BMIs of 49–50 were free of pulmonary disease and had A-aO2 gradients of 22.6 ± 2.838 and 19 ± 9 mm Hg,40 respectively. Therefore, although obesity can cause a mild widening of the A-aO2 gradient, this is not sufficient to cause frank hypoxaemia.
The widening of the A-aO2 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-aO2 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 PaO2 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 PaO2, PaCO2 and A-aO2 gradient.40
Gas exchange (DLCO) seems to be relatively well preserved in subjects with simple obesity.8,19,22,44,45 When corrected for lung volume (DLCO/VA), values may be elevated in extremely obese (height/weight ratio >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 DLCO/VA were examined retrospectively showed that a reduction in VC was a common finding, and that obesity was a common cause of this reduction.46 DLCO/VA may be increased in obese patients due to an increase in pulmonary blood volume8,46
Since obese individuals have a higher basal metabolic rate (VO2) 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 VO2 to work rate lines are the same as in normal-weight individuals, implying that it is the increase in basal rate that is responsible for the increase in VO2 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-aO2 gradient, and PaO2 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-aO2 gradient.51
In addition to having a lower A-aO2 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 44.8 ± 1.3 kg/m2) 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 VO2 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.
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 16 171 participants showed that obesity was a risk factor for self-reported dyspnoea. Individuals in the highest quintile of BMI (>31.0 kg/m2) had an odds ratio of 2.66 (95% CI 2.35–3.00, P = 0.001) for reporting dyspnoea when walking up a hill, as compared with those in the control quintile (BMI 22.1–24.8 kg/m2). 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 (47.5 ± 7 and 48.7 ± 6 kg/m2, 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 performance23,55 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/m2) and eight without (BMI 36 ± 5 kg/m2), 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.
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/m2 after a very low calorie diet.60 Even modest weight loss (reduction in BMI from 35 to 33 kg/m2) leads to modest but significant improvements in ERV.33 FRC and TLC also improve to varying degrees.16,18,38,59,60 The A-aO2 gradient also tends to improve if ΔBMI is >20 kg/m2 after jejunoileal bypass. The ΔA-aO2 gradient is linearly correlated with ΔBMI.39 This supports the hypothesis that a widened A-aO2 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 47.3 ± 7.2 to 31.8 ± 5.1 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 obese patients experience dyspnoea, whereas others do not.
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.