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Published in final edited form as: Respir Physiol Neurobiol. 2013 May 21;189(2):10.1016/j.resp.2013.05.019. doi: 10.1016/j.resp.2013.05.019

OBESITY: CHALLENGES TO VENTILATORY CONTROL DURING EXERCISE A BRIEF REVIEW

Tony G Babb 1
PMCID: PMC3797147  NIHMSID: NIHMS491503  PMID: 23707540

Abstract

Obesity is a national health issue in the US. Among the many physiological changes induced by obesity, it also presents a unique challenge to ventilatory control during exercise due to increased metabolic demand of moving larger limbs, increased work of breathing due to extra weight on the chest wall, and changes in breathing mechanics. These challenges to ventilatory control in obesity can be inconspicuous or overt among obese adults but for the most part adaptation of ventilatory control during exercise in obesity appears remarkably unnoticed in the majority of obese people. In this brief review, the changes to ventilatory control required for maintaining normal ventilation during exercise will be examined, especially the interaction between respiratory neural drive and ventilation. Also, gaps in our current knowledge will be discussed.

Keywords: Respiratory neural drive, respiratory neural output, ventilation, ventilatory response to exercise, gas exchange, exercise hyperpnea

1. INTRODUCTION

Obesity presents a unique challenge to ventilatory control during exercise due to increased metabolic demand of moving larger limbs, increased work of breathing due to extra weight on the thorax, and changes in breathing mechanics. However, the effects of obesity are not homogeneous among all obese individuals as is often thought. Obesity-related effects may vary depending on the magnitude of obesity, differences in fat distribution, variability of changes in lung function, age, gender, and underlying comorbidities, etc. Thus, the effect of obesity must be individualized rather than generalized in many obese adults. Also, the effects of obesity can be simple in otherwise healthy individuals or very complex in obese patients with obesity-related complaints and/or multiple comorbidities. Therefore, the challenge to ventilatory control in obesity can be inconspicuous or overt among obese adults although in most cases adaptation of ventilatory control during exercise appears remarkably seamless in the majority of obese people.

Ventilatory control adaptations provoked by obesity may seem seamless because it is not always possible to recognize or measure the adjustment in ventilatory control or respiratory neural drive based upon measured ventilation. Ventilation is usually a surrogate marker of respiratory neural drive or respiratory neural output needed to generate that ventilation. However, in obesity ventilation is usually within normal limits relative to increased oxygen demand (Whipp and Davis, 1984) but respiratory neural drive is probably not. Neural drive is augmented in order to yield normal ventilation in the face of increased respiratory mechanical loads (i.e., increased respiratory impedance) on the chest wall (i.e., rib cage and abdomen). If neural drive were not increased in proportion to the increased work of breathing and/or mechanical constraints, there would be a dramatic shortfall in ventilation. This can be seen at rest in patients with obesity hypoventilation syndrome (OHS) when demand and control are not correctly coupled. However, the increase in respiratory neural drive may have a cost related to the perception of breathing, breathing discomfort, and/or an increased awareness of the work/effort of breathing. The challenges to ventilatory control in patients with complex obesity-related problems like sleep disordered breathing, sleep apnea, and OHS demand reviews of their own and will not be discussed at length in this brief review.

2. VENTILATORY CONTROL DURING EXERCISE

The normal exercise ventilatory response can be viewed as a primary feedforward exercise stimulus (Figure 1), modified by CO2-chemoreceptor feedback to minimize changes in the arterial partial pressure of carbon dioxide (PCO2) from rest to exercise (Eldridge, 1994; Forster, 2000; Mitchell et al., 1993; Mitchell and Babb, 2006; Turner et al., 1997). The primary exercise stimulus operates in a feedforward manner with respect to arterial PCO2 regulation (Houk, 1988), yet it remains poorly understood despite decades of study (Casaburi, 2012; Forster ,2000; McIlroy, 1959). Many investigations have focused on the hypothesis that the primary stimulus results from a neurogenic component, arising in the central nervous system or periphery, and most likely represents a combination of factors (Eldridge ,1994; Forster ,2000; Mitchell et al. 1993). If arterial PCO2 increases or decreases for any reason during exercise, CO2-chemoreceptor feedback will adjust the exercise ventilatory response, thereby minimizing changes in arterial PCO2 from rest to exercise (Babb, 1997a; Babb, 1997b; Babb et al., 2003; Forster et al., 1993). Collectively, the primary exercise stimulus and chemoreceptor feedback maintain arterial PCO2 with minimal disruption in homeostasis during mild-to-moderate exercise (Bennett and Fordyce, 1985; Mitchell, 1990).

Figure 1.

Figure 1

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Schematic representative of ventilatory control during exercise.

The normal ventilatory response to exercise is linear up to approximately 50% of peak exercise. Beyond this level, the increase in V̇E becomes nonlinear with work (e.g., oxygen uptake, V̇O2, or work rate). In general, a low ventilatory response could indicate mechanical ventilatory constraints. Likewise, an excess ventilatory response to exercise could indicate increased ventilatory demand (i.e., increased dead space or ventilatory inefficiency). The “break point” in the ventilatory response to exercise is referred to as the ventilatory threshold (VTh), although the mechanism of VTh remains controversial. Nevertheless, locating a VTh is helpful to indentify submaximal from heavy exercise. The ventilatory response to exercise from rest to exercise is defined by the change in V̇E divided by the change in expired carbon dioxide (ΔV̇E / ΔV̇CO2) or by V̇E / V̇CO2 at the VTh (Sun et al., 2002).

However, if environmental or physiological conditions change (e.g., obesity), an adjustment in the ventilatory response is required to maintain similar regulation of arterial blood gases. Without such adjustments, less precise arterial PCO2 regulation would result (Mitchell ,1990). Thus, an additional feature of the exercise ventilatory response is revealed with experimental perturbations that alter resting ventilatory drive and blood gases (Mitchell et al., 1984; Mitchell and Johnson, 2003). For example, with increased respiratory dead space, the exercise ventilatory response is increased in female goats (Mitchell ,1990), thereby maintaining arterial PCO2 regulation from rest to exercise. This modulation of the exercise ventilatory response has been shown recently in nonobese humans (Poon, 1992; Wood et al., 2008a; Wood et al., 2010; Wood et al., 2011) although the mechanism has not been elucidated. However, these findings suggest that the feedforward primary exercise stimulus can be modulated as part of an adaptive control strategy and possibly occurs at the level of the spinal cord (Babb et al., 2010; Mitchell et al. 1993; Mitchell and Babb ,2006). These findings have not been confirmed in obese adults but theoretically could be an important factor in the adjustment of ventilatory control during exercise in obese adults (i.e., possibly increased respiratory neural drive).

Furthermore, there is evidence that adaptive control changes in the exercise ventilatory response can occur on a long-term basis in response to chronic dead space loading during exercise or with chronic respiratory resistive loading of the airways during repeated exercise bouts (Martin and Mitchell, 1993; Turner and Stewart, 2004; Wood et al., 2003). Thus, it is in theory, possible that ventilatory control during exercise in obesity is an ongoing adaptive process where ventilation is well preserved via increased respiratory neural output until underlying disease develops or until adaptive control processes are overwhelmed or exhausted by additional weight gain (i.e., sleep apnea, OHS). Further study of these possibilities is required since these are novel and understudied areas, especially in obese adults.

3. VENTILATORY CONTROL DURING REST IN OBESITY

Respiratory neural drive appears increased in obese adults at rest as demonstrated by increased P0.1 (i.e., pressure developed at the mouth 100 ms after onset of an occluded inspiration), and/or diaphragmatic electromyogram activity (EMGdi) (Burki and Baker, 1984; Chlif et al., 2007; Chlif et al., 2009; Lopata and Onal, 1982; Sampson and Grassino, 1983a; Steier et al., 2009). While there are limitations for estimating respiratory neural drive with both of these methods (Luo and Moxham, 2005; Whitelaw and Derenne, 1993), these are the only indicators of respiratory neural output that are available. Also, nonobese and obese subjects are not always compared at the same ventilatory level, which complicates the interpretation of neural drive. Tidal volume (VT) and inspiratory time (TI) are lower in obese subjects, but the mean inspiratory flow rate (VT/TI) remains unchanged (Burki and Baker ,1984; Chlif et al. 2007; Chlif et al. 2009; Sampson and Grassino ,1983a).

The proposed explanations for the increase in P0.1 include increased central inspiratory drive, respiratory muscle insufficiency including possibly respiratory muscle weakness (also disadvantageous chest-wall configuration), and/or breathing at low lung volumes (i.e., where increased force generation is possible for any given level of neural drive - greater mechanical advantage) (Chlif et al. 2009; Sampson and Grassino ,1983a; Wang and Cerny, 2004). The most likely explanation for the increased P0.1 is augmented respiratory neural drive in response to the increased weight on the thorax (Figure 1, respiratory impedance is increased) (Lopata and Onal ,1982; Sampson and Grassino ,1983a; Wang and Cerny ,2004). This seems reasonable in light of the necessity for ventilation to remain within normal limits (i.e., ventilatory homeostasis), which is the primary goal of ventilatory control. Plus, respiratory muscle function is not consistently nor remarkably impaired in obese adults and the work of breathing is notably increased, demanding both increased muscle activity and respiratory neural output (Luce, 1980). However, the increase in respiratory neural drive is not enough to completely restore VT but the associated decrease in TI allows Fb to compensate thereby yielding a normal level of ventilation relative to the increase in oxygen uptake (i.e., TI/Ttot remains relatively unchanged with obesity) (Sampson and Grassino ,1983a). Plus, among subjects the magnitude of P0.1 is closely related to the increase in ideal body weight (Sampson and Grassino ,1983a) and the increase in EMGdi (%max) is closely associated with BMI (Steier et al. 2009).

However, the mechanism of this increased respiratory neural drive has not been elucidated but could be the result of reflex and conscious mechanisms (Lopata and Onal ,1982) or theoretically long term adaptive learning in response to the increase in mass loading (Babb et al. 2010; Mitchell et al. 1993; Mitchell and Babb ,2006). As part of this latter theory, anything that increases resting respiratory drive should also result in increased respiratory neural drive during subsequent exercise in order to keep the ventilatory response from rest to exercise normal (Bach et al., 1993; Dempsey et al., 1984; Mitchell et al. 1984). This has not been studied in obesity.

In summary, ventilation is usually normal in otherwise healthy obese adults at rest probably due to an increase in respiratory neural drive, which is proportional to the increased respiratory impedance due to weight gain on the thorax (i.e., increased BMI).

4. VENTILATORY CONTROL DURING EXERCISE IN OBESITY

The metabolic demand of exercise in obesity is increased (Figure 2) and therefore the ventilation for a given work rate is increased (Babb et al., 1991; Dempsey et al., 1966a; Ofir et al., 2007; Wasserman and Whipp, 1975). However, when compared with increased oxygen uptake and carbon dioxide output, ventilation is normal and the ventilatory response to exercise is usually normal in otherwise healthy obese adults, and even in morbidly obese individuals (Figure 3) (Babb et al. 1991; Ofir et al. 2007; Whipp and Davis ,1984; Wood et al., 2008b). As a result, the arterial PCO2 remains within normal limits in obese adults, although the partial pressure of arterial oxygen (PO2) may be slightly lower at rest and during exercise (Bernhardt et al., 2012; Zavorsky and Hoffman, 2008). However, there is no significant arterial desaturation during submaximal exercise in otherwise healthy mildly, moderately, or morbidly obese patients (Zavorsky and Hoffman ,2008). At peak exercise it has been reported that ventilation may not be as high as usually observed in nonobese adults (Zavorsky et al., 2007). This interpretation is based on the minimal fall in arterial PCO2 at near peak, and peak exercise, although arterial PCO2 is still within normal limits (Zavorsky et al. 2007). Therefore, the ventilatory response to exercise is quite normal in most obese adults, which implies that ventilatory control is able to adapt to obesity-related changes in respiratory function and chest wall loading (i.e., increased respiratory impedance due to fat weight on the chest wall).

Figure 2.

Figure 2

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Schematic representative of oxygen uptake (V̇O2) vs. work rate (W) relationship in nonobese and obese adults. Figure based on data extracted from Salvadori et al., 2008.

Figure 3.

Figure 3

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Schematic representative of ventilation (V̇E) vs. carbon dioxide output (V̇CO2) relationship during submaximal exercise in nonobese and obese adults. Figure based on data extracted from Salvadori et al., 2008.

For any level of ventilation, VT is usually smaller (Figure 4) and Fb is higher in obese adults during exercise (Figure 5) (Babb et al. 1991; Dempsey et al., 1966b; Ofir et al. 2007) just as it is at rest (Chlif et al. 2009; Sampson and Grassino ,1983a). This is thought to be a way to minimize the elastic work of breathing at the expense of increased resistive work, but the Fb is probably not high enough during exercise to make much of a difference in the work of breathing (Milic-Emili et al., 1960). The change in breathing pattern is likely due to the increased weight on the thorax as shown in simulated obesity by chest wall loading (Wang and Cerny ,2004) or inertial loading (Brown et al., 1990). Operational lung volumes are altered slightly in obese adults with end-expiratory lung volume starting lower at rest only to rise to near normal levels during peak exercise, and end-inspiratory lung volume increases slightly less than in normal weight subjects (Babb et al., 1989; Babb, 1999; Babb et al., 2002; Babb et al., 2011; DeLorey et al., 2005; Ofir et al. 2007; Romagnoli et al., 2008). Thus, breathing mechanics are markedly altered with obesity but it appears that there are no limitations to adequate control of ventilation. However, the increased energy required to generate ventilation could increase the perception or discomfort with breathing (Babb et al., 2008; Ofir et al. 2007; Romagnoli et al. 2008) and it has been shown that proportional assisted ventilation, which decreases the inspiratory work of breathing, can increase exercise performance and reduce dyspnea in obese adults during exercise (Dreher et al., 2010).

Figure 4.

Figure 4

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Schematic representative of tidal volume (VT) vs. ventilation (V̇E) relationship in nonobese and obese adults. Figure based on data estimated from Babb et al., 1991.

Figure 5.

Figure 5

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Schematic representative of breathing frequency (Fb) vs. ventilation (V̇E) relationship in nonobese and obese adults. Figure based on data estimated from Babb et al., 1991.

During exercise, like rest, respiratory neural drive is also increased in obese adults as demonstrated by an augmented P0.1 (Figure 6) (Chlif et al. 2007; Chlif et al. 2009). As a result, the ventilatory response to exercise remains normal (Babb et al. 1991; Ofir et al. 2007; Salvadori et al., 2008; Whipp and Davis ,1984) and VT/TI and TI/Ttot are relatively unchanged (Figures 7 and 8) (Chlif et al. 2007; Chlif et al. 2009). However, few investigations have studied this in detail. Also, the ventilatory response to exercise has been reported as normal even in patients with OHS (Menitove et al., 1984). These findings suggest that even in clinical patients where central CO2 sensitivity is obviously and dramatically impaired (i.e., OHS patients), the exercise ventilatory response remains within normal limits. Interestingly, overweight patients with obstructive sleep apnea are reported to have an elevated ventilatory response (Hargens et al., 2009). In contrast to the explanation proposed by the authors, it is unlikely that the exaggerated ventilatory response is due to changes in chemosensitivity since impaired sensitivity in OHS patients has no effect on the exercise ventilatory response and the arterial PCO2 changes little from rest to exercise in obese patients. However, this important finding should be studied further given the number of overweight and obese men and women with sleep apnea.

Figure 6.

Figure 6

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Schematic representative of mouth occlusion pressure (P0.1) vs. ventilation (V̇E) relationship in nonobese and obese adults. Figure based on a compilation of data estimated from Salvadori et al., 2008, Chlif et al., 2007, and Sampson and Grassino, 1983.

Figure 7.

Figure 7

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Schematic representative of breathing duty cycle (TI / TTot) vs. ventilation (V̇E) relationship in nonobese and obese adults. Figure based on a compilation data estimated from Salvadori et al., 2008 and Chlif et al., 2007.

Figure 8.

Figure 8

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Schematic representative of mean inspiratory flow rate (VT / TI) vs. ventilation (V̇E) relationship in nonobese and obese adults. Figure based on a compilation data estimated from Salvadori et al., 2008 and Chlif et al., 2007.

In summary, despite increased metabolic demand, increased work of breathing, and changes in breathing mechanics, ventilation is mostly within normal limits during exercise due to an increase respiratory neural drive, which is necessary to generate normal ventilation.

5. VENTILATORY RESPONSIVENESS AT REST IN OBESITY

Unlike exercise, chemosensitivity at rest has been studied extensively, yet there are conflicting findings in obesity. Some investigations have reported increased (Ge et al., 2005; Narkiewicz et al., 1999), normal (Chapman et al., 1990; Kronenberg et al., 1975; Nishibayashi et al., 1987), or decreased (Kunitomo et al., 1988; Zwillich et al., 1975) ventilatory responses to hypercapnia and hypoxia in obesity. These differences in responses could be related to age bias, differences in mechanical ventilatory limitations, differences in the magnitude of obesity, presence or absence of OHS or obstructive sleep apnea (OSA), and even an increased oxygen cost of breathing (Crummy et al., 2008; Piper and Grunstein, 2010; Salome et al., 2010). Also, it has been reported that the ventilatory response to inhaled CO2 can be decreased after marked weight loss due to a reduction in the oxygen cost of breathing and decreased ventilatory demand (Emirgil and Sobol, 1973). Others may even suggest that chemo-responsiveness has not been measured correctly in many of these studies (Duffin, 2011; Pedersen et al., 1999). Therefore, there is not a consensus of the effects of obesity on chemosensitivity in otherwise healthy obese adults and further studies are needed using newer techniques.

As stated earlier, it has been shown in at least one publication that there is an absence of relationship between ventilatory responsiveness at rest and the ventilatory response to exercise even in patients with OHS (Menitove et al. 1984), which is in agreement with conventional thinking in adults (Dempsey et al. 1984). Most investigations of chemosensitivity in obesity are concerned with the responses of patients with OHS, which has growing clinical importance and will be discussed only briefly here. Another observation of interest regarding chemosensitivity in obesity is the finding that exaggerated respiratory chemosensitivity may be associated with arterial oxygen saturation at altitude and acute mountain sickness in relatively mildly obese men (Ge et al., 2003; Ge et al. 2005). Considering over 60% of the US population is either overweight or obese and many have easy access to leisure activities at altitude, this finding begs further investigation.

Only a few studies have estimated respiratory neural drive in obesity during chemosensitivity testing. In a very detailed study, neural respiratory drive (P0.1) was reported to be increased in otherwise healthy obese patients during CO2 rebreathing, despite a blunted ventilatory response as compared with normal weight controls (Sampson and Grassino, 1983b). In contrast, age-, height-, and weight-matched former OHS patients were reported to have an even more blunted ventilatory response to inhaled CO2 and also to have a decreased respiratory neural drive (Sampson and Grassino ,1983b). It was suggested that both increased neural drive and improved diaphragmatic configuration (i.e., lower FRC), led to increased neuromuscular drive in the simple obese patients in order to maintain adequate ventilation in the presence of increased chest wall load (Sampson and Grassino ,1983b).

In a related study, it has been reported that OHS patients have a reduced ventilatory response to CO2 as compared with former OHS patients and simple obese patients (Lopata et al., 1979). Mean occlusion pressure after 150 ms was not found to be different among OHS, former OHS, or otherwise healthy obese adults but the variability within groups was quite large and the sample sizes were modest as noted above. Nevertheless, diaphragmatic EMGdi confirmed these inconsistent findings in this study. In a later paper by Lopata and others, it was reported that the ventilatory response to CO2 rebreathing, while within normal limits in obese patients, it was lower than in nonobese controls, but higher than observed in OSA or OHS patients (Lopata and Onal ,1982). However, P0.15 was within normal limits in the otherwise healthy obese subjects and similar to nonobese subjects while occlusion pressure was much lower in obese patients with OSA and OHS during CO2 rebreathing. Mean EMGdi was increased in the obese over that in the nonobese subjects and the patients with OSA and OHS who had similar values.

The conclusion from these findings was that obese adults have a lower ventilatory responsiveness but an increase in respiratory neural drive and decrease in neuromuscular coupling efficiency. It appears that in obese adults, respiratory drive can be increased during CO2 rebreathing but not enough to completely overcome the load on the chest wall and thus they have a lower ventilatory response than seen in nonobese controls.

In general, it would appear that obese patients who are unable to activate the respiratory muscles in proportion to chest wall loads during CO2 rebreathing (i.e., OHS patients) may be prone to respiratory failure in the long term (Lopata and Onal ,1982; Lourenco, 1969; Parameswaran et al., 2006). Without more extensive data, it is difficult to generalize these reports into an overall consensus. However, it would seem that in obese patients who are responsive to CO2 inhalation or CO2 rebreathing, respiratory neural drive will be increased, but like quiet breathing at rest, ventilation may be increased, normal, or decreased probably depending on the magnitude of obesity, the degree of obesity-related effects on respiratory function, the oxygen cost of breathing, respiratory neuromuscular coupling efficiency, and the load on the chest wall. Patients, who are not responsive to CO2 inhalation or rebreathing, will probably not increase respiratory neural drive and will be at the most risk for long term respiratory failure. However, this is a very complex issue and it is difficult to sort out whether changes in respiratory drive, respiratory muscle activity, neuromuscular coupling, and ventilation occur in obese adults at rest or during exercise.

6. SUMMARY

A caveat to this review is the limited amount of studies and data available on ventilatory control during exercise in obesity, OHS, and obese sleep apnea patients. However, exercise training and regular physical activity are major components in the fight of weight balance, gain, and loss. Also, exercise is the largest ventilatory challenge to the respiratory system in adults and the exercise ventilatory response remains remarkably normal in simple and complex obesity. Nevertheless, we know very little about the details of exercise ventilatory control in obese patients who have such notable changes in metabolic demands, ventilatory requirements, gas exchange, breathing pattern, and respiratory mechanics. The bottom line is that adaptive ventilatory strategies during exercise appear quite impressive in maintaining appropriate ventilatory homeostasis in mildly, moderately, and/or extremely otherwise healthy obese adults.

HIGHLIGHTS.

VENTILATORY CONTROL DURING EXERCISE

VENTILATORY CONTROL DURING REST IN OBESITY

VENTILATORY CONTROL DURING EXERCISE IN OBESITY

VENTILATORY RESPONSIVENESS AT REST IN OBESITY

ACKNOWLEDGMENTS

The author wishes to thank Joseph Genovese for his assistance in preparing the figures and Drs Vipa Bernhardt and Matthew Spencer for their editorial comments on the review. This publication was supported in part by NIH HL-096782, King Charitable Foundation Trust, Susan Lay Atwell Gift for Pulmonary Research, Cain Foundation, and Texas Health Presbyterian Hospital Dallas.

Footnotes

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