Contents lists available at SciVerse ScienceDirect
Respiratory Physiology & Neurobiology
j ourna l ho me pa ge: www.elsev ier .com/ loca te / resphys io l
eview
besity: Challenges to ventilatory control during exercise—A brief review�
ony G. Babb ∗
nstitute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas and Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine,niversity of Texas Southwestern Medical Center, Dallas, TX 75231, United States
a r t i c l e i n f o
rticle history:ccepted 15 May 2013
a b s t r a c t
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 metabolicdemand of moving larger limbs, increased work of breathing due to extra weight on the chest wall, and
eywords:espiratory neural driveespiratory neural outputentilationentilatory response to exerciseas exchangexercise hyperpnea
changes in breathing mechanics. These challenges to ventilatory control in obesity can be inconspicuousor overt among obese adults but for the most part adaptation of ventilatory control during exercise inobesity appears remarkably unnoticed in the majority of obese people. In this brief review, the changesto 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 currentknowledge will be discussed.
. Introduction
Obesity presents a unique challenge to ventilatory control dur-ng exercise due to increased metabolic demand of moving largerimbs, increased work of breathing due to extra weight on the tho-ax, and changes in breathing mechanics. However, the effects ofbesity are not homogeneous among all obese individuals as isften thought. Obesity-related effects may vary depending on theagnitude of obesity, differences in fat distribution, variability of
hanges in lung function, age, gender, and underlying comorbidi-ies, etc. Thus, the effect of obesity must be individualized ratherhan generalized in many obese adults. Also, the effects of obesityan be simple in otherwise healthy individuals or very complexn obese patients with obesity-related complaints and/or multi-le comorbidities. Therefore, the challenge to ventilatory control inbesity can be inconspicuous or overt among obese adults althoughn most cases adaptation of ventilatory control during exerciseppears remarkably seamless in the majority of obese people.
Ventilatory control adaptations provoked by obesity may seemeamless because it is not always possible to recognize or mea-
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
ure the adjustment in ventilatory control or respiratory neuralrive based upon measured ventilation. Ventilation is usually aurrogate marker of respiratory neural drive or respiratory neural
� This paper is part of a special issue entitled “Clinical Challenges to Ventilatoryontrol”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracyaker-Herman and Dr. David Paydarfar.∗ Correspondence address: Institute for Exercise and Environmental Medicine,
output needed to generate that ventilation. However, in obesityventilation is usually within normal limits relative to increasedoxygen demand (Whipp and Davis, 1984) but respiratory neuraldrive is probably not. Neural drive is augmented in order to yieldnormal ventilation in the face of increased respiratory mechani-cal loads (i.e., increased respiratory impedance) on the chest wall(i.e., rib cage and abdomen). If neural drive were not increased inproportion to the increased work of breathing and/or mechani-cal constraints, there would be a dramatic shortfall in ventilation.This can be seen at rest in patients with obesity hypoventilationsyndrome (OHS) when demand and control are not correctly cou-pled. However, the increase in respiratory neural drive may have acost related to the perception of breathing, breathing discomfort,and/or an increased awareness of the work/effort of breathing. Thechallenges to ventilatory control in patients with complex obesity-related problems like sleep disordered breathing, sleep apnea, andOHS demand reviews of their own and will not be discussed atlength in this brief review.
2. Ventilatory control during exercise
The normal exercise ventilatory response can be viewed asa primary feedforward exercise stimulus (Fig. 1), modified byCO2-chemoreceptor feedback to minimize changes in the arterialpartial pressure of carbon dioxide (PCO2) from rest to exercise(Eldridge, 1994; Forster, 2000; Mitchell et al., 1993; Mitchell andBabb, 2006; Turner et al., 1997). The primary exercise stimulus
ry control during exercise—A brief review. Respir. Physiol. Neurobiol.
operates in a feedforward manner with respect to arterial PCO2regulation (Houk, 1988), yet it remains poorly understood despitedecades of study (Casaburi, 2012; Forster, 2000; McIlroy, 1959).Many investigations have focused on the hypothesis that the
rimary stimulus results from a neurogenic component, arisingn the central nervous system or periphery, and most likely rep-esents a combination of factors (Eldridge, 1994; Forster, 2000;itchell et al., 1993). If arterial PCO2 increases or decreases for any
eason during exercise, CO2-chemoreceptor feedback will adjusthe exercise ventilatory response, thereby minimizing changesn arterial PCO2 from rest to exercise (Babb, 1997a,b; Babb et al.,003; Forster et al., 1993). Collectively, the primary exercisetimulus and chemoreceptor feedback maintain arterial PCO2ith minimal disruption in homeostasis during mild-to-moderate
xercise (Bennett and Fordyce, 1985; Mitchell, 1990).The normal ventilatory response to exercise is linear up to
pproximately 50% of peak exercise. Beyond this level, the increasen V̇E becomes nonlinear with work (e.g., oxygen uptake, V̇O2, or
ork rate). In general, a low ventilatory response could indicateechanical ventilatory constraints. Likewise, an excess ventilatory
esponse to exercise could indicate increased ventilatory demandi.e., increased dead space or ventilatory inefficiency). The “breakoint” in the ventilatory response to exercise is referred to as theentilatory threshold (VTh), although the mechanism of VTh remainsontroversial. Nevertheless, locating a VTh is helpful to indentifyubmaximal from heavy exercise. The ventilatory response to exer-ise from rest to exercise is defined by the change in V̇E divided byhe change in expired carbon dioxide (�V̇E/�V̇CO2) or by V̇E/V̇CO2t the VTh (Sun et al., 2002).
However, if environmental or physiological conditions changee.g., obesity), an adjustment in the ventilatory response is requiredo maintain similar regulation of arterial blood gases. Withoutuch adjustments, less precise arterial PCO2 regulation would
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
esult (Mitchell, 1990). Thus, an additional feature of the exerciseentilatory response is revealed with experimental perturbationshat alter resting ventilatory drive and blood gases (Mitchell et al.,984; Mitchell and Johnson, 2003). For example, with increased
tilatory control during exercise.
respiratory dead space, the exercise ventilatory response isincreased in female goats (Mitchell, 1990), thereby maintainingarterial PCO2 regulation from rest to exercise. This modulationof the exercise ventilatory response has been shown recently innonobese humans (Poon, 1992; Wood et al., 2008a; Wood et al.,2010; Wood et al., 2011) although the mechanism has not beenelucidated. However, these findings suggest that the feedforwardprimary exercise stimulus can be modulated as part of an adaptivecontrol strategy and possibly occurs at the level of the spinalcord (Babb et al., 2010; Mitchell et al., 1993; Mitchell and Babb,2006). These findings have not been confirmed in obese adults buttheoretically could be an important factor in the adjustment ofventilatory control during exercise in obese adults (i.e., possiblyincreased respiratory neural drive).
Furthermore, there is evidence that adaptive control changes inthe exercise ventilatory response can occur on a long-term basisin response to chronic dead space loading during exercise or withchronic respiratory resistive loading of the airways during repeatedexercise bouts (Martin and Mitchell, 1993; Turner and Stewart,2004; Wood et al., 2003). Thus, it is in theory, possible that ven-tilatory control during exercise in obesity is an ongoing adaptiveprocess where ventilation is well preserved via increased respi-ratory neural output until underlying disease develops or untiladaptive control processes are overwhelmed or exhausted by addi-tional weight gain (i.e., sleep apnea, OHS). Further study of thesepossibilities is required since these are novel and understudiedareas, especially in obese adults.
3. Ventilatory control during rest in obesity
ry control during exercise—A brief review. Respir. Physiol. Neurobiol.
Respiratory neural drive appears increased in obese adults atrest as demonstrated by increased P0.1 (i.e., pressure developed atthe mouth 100 ms after onset of an occluded inspiration), and/or
ulated obesity by chest wall loading (Wang and Cerny, 2004) orinertial loading (Brown et al., 1990). Operational lung volumes arealtered slightly in obese adults with end-expiratory lung volumestarting lower at rest only to rise to near normal levels during
ARTICLEESPNB-2092; No. of Pages 7
T.G. Babb / Respiratory Physiolog
iaphragmatic electromyogram activity (EMGdi) (Burki and Baker,984; Chlif et al., 2007, 2009; Lopata and Onal, 1982; Sampson andrassino, 1983a; Steier et al., 2009). While there are limitations
or estimating respiratory neural drive with both of these meth-ds (Luo and Moxham, 2005; Whitelaw and Derenne, 1993), thesere the only indicators of respiratory neural output that are avail-ble. Also, nonobese and obese subjects are not always comparedt the same ventilatory level, which complicates the interpreta-ion of neural drive. Tidal volume (VT) and inspiratory time (TI) areower in obese subjects, but the mean inspiratory flow rate (VT/TI)emains unchanged (Burki and Baker, 1984; Chlif et al., 2007, 2009;ampson and Grassino, 1983a).
The proposed explanations for the increase in P0.1 includencreased central inspiratory drive, respiratory muscle insuf-ciency including possibly respiratory muscle weakness (alsoisadvantageous chest-wall configuration), and/or breathing at low
ung volumes (i.e., where increased force generation is possibleor any given level of neural drive – greater mechanical advan-age) (Chlif et al., 2009; Sampson and Grassino, 1983a; Wangnd Cerny, 2004). The most likely explanation for the increased0.1 is augmented respiratory neural drive in response to thencreased weight on the thorax (Fig. 1, respiratory impedance isncreased) (Lopata and Onal, 1982; Sampson and Grassino, 1983a;
ang and Cerny, 2004). This seems reasonable in light of theecessity for ventilation to remain within normal limits (i.e., ven-ilatory homeostasis), which is the primary goal of ventilatoryontrol. Plus, respiratory muscle function is not consistently noremarkably impaired in obese adults and the work of breathing isotably increased, demanding both increased muscle activity andespiratory neural output (Luce, 1980). However, the increase inespiratory neural drive is not enough to completely restore VTut the associated decrease in TI allows Fb to compensate therebyielding a normal level of ventilation relative to the increase in oxy-en uptake (i.e., TI/Ttot remains relatively unchanged with obesity)Sampson and Grassino, 1983a). Plus, among subjects the magni-ude of P0.1 is closely related to the increase in ideal body weightSampson and Grassino, 1983a) and the increase in EMGdi (%max)s closely associated with BMI (Steier et al., 2009).
However, the mechanism of this increased respiratory neuralrive has not been elucidated but could be the result of reflex andonscious mechanisms (Lopata and Onal, 1982) or theoreticallyong term adaptive learning in response to the increase in massoading (Babb et al., 2010; Mitchell et al., 1993; Mitchell and Babb,006). As part of this latter theory, anything that increases restingespiratory drive should also result in increased respiratory neuralrive during subsequent exercise in order to keep the ventilatoryesponse from rest to exercise normal (Bach et al., 1993; Dempseyt al., 1984; Mitchell et al., 1984). This has not been studied inbesity.
In summary, ventilation is usually normal in otherwise healthybese adults at rest probably due to an increase in respiratoryeural drive, which is proportional to the increased respiratory
mpedance due to weight gain on the thorax (i.e., increased BMI).
. Ventilatory control during exercise in obesity
The metabolic demand of exercise in obesity is increased (Fig. 2)nd therefore the ventilation for a given work rate is increasedBabb et al., 1991; Dempsey et al., 1966a; Ofir et al., 2007;
asserman and Whipp, 1975). However, when compared withncreased oxygen uptake and carbon dioxide output, ventilation
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
s normal and the ventilatory response to exercise is usually nor-al in otherwise healthy obese adults, and even in morbidly obese
ndividuals (Fig. 3) (Babb et al., 1991; Ofir et al., 2007; Whipp andavis, 1984; Wood et al., 2008b). As a result, the arterial PCO2
Fig. 2. Schematic representative of oxygen uptake (V̇O2) vs. work rate (W) relation-ship in nonobese and obese adults. Figure based on data extracted from Salvadoriet al. (2008).
remains within normal limits in obese adults, although the par-tial pressure of arterial oxygen (PO2) may be slightly lower at restand during exercise (Bernhardt et al., 2013; Zavorsky and Hoffman,2008). However, there is no significant arterial desaturation dur-ing submaximal exercise in otherwise healthy mildly, moderately,or morbidly obese patients (Zavorsky and Hoffman, 2008). At peakexercise it has been reported that ventilation may not be as highas usually observed in nonobese adults (Zavorsky et al., 2007).This interpretation is based on the minimal fall in arterial PCO2at near peak, and peak exercise, although arterial PCO2 is stillwithin normal limits (Zavorsky et al., 2007). Therefore, the ven-tilatory 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 chestwall).
For any level of ventilation, VT is usually smaller (Fig. 4) and Fbis higher in obese adults during exercise (Fig. 5) (Babb et al., 1991;Dempsey et al., 1966b; Ofir et al., 2007) just as it is at rest (Chlifet al., 2009; Sampson and Grassino, 1983a). This is thought to bea way to minimize the elastic work of breathing at the expenseof increased resistive work, but the Fb is probably not high enoughduring exercise to make much of a difference in the work of breath-ing (Milic-Emili et al., 1960). The change in breathing pattern islikely due to the increased weight on the thorax as shown in sim-
ry control during exercise—A brief review. Respir. Physiol. Neurobiol.
Fig. 3. Schematic representative of ventilation (V̇E) vs. carbon dioxide output (V̇CO2)relationship during submaximal exercise in nonobese and obese adults. Figure basedon data extracted from Salvadori et al. (2008).
Fig. 6. Schematic representative of mouth occlusion pressure (P0.1) vs. ventilation(V̇E) relationship in nonobese and obese adults. Figure based on a compilation ofdata estimated from Salvadori et al. (2008), Chlif et al. (2007), and Sampson andGrassino, 1983a,b.
ig. 4. Schematic representative of tidal volume (VT) vs. ventilation (V̇E) relationshipn nonobese and obese adults. Figure based on data estimated from Babb et al. (1991).
eak exercise, and end-inspiratory lung volume increases slightlyess than in normal weight subjects (Babb et al., 1989, 2002, 2011;abb, 1999; DeLorey et al., 2005; Ofir et al., 2007; Romagnoli et al.,008). Thus, breathing mechanics are markedly altered with obe-ity but it appears that there are no limitations to adequate controlf ventilation. However, the increased energy required to gener-te ventilation could increase the perception or discomfort withreathing (Babb et al., 2008; Ofir et al., 2007; Romagnoli et al., 2008)nd it has been shown that proportional assisted ventilation, whichecreases the inspiratory work of breathing, can increase exerciseerformance and reduce dyspnea in obese adults during exerciseDreher et al., 2010).
During exercise, like rest, respiratory neural drive is alsoncreased in obese adults as demonstrated by an augmented P0.1Fig. 6) (Chlif et al., 2007, 2009). As a result, the ventilatory responseo exercise remains normal (Babb et al., 1991; Ofir et al., 2007;alvadori et al., 2008; Whipp and Davis, 1984) and VT/TI and TI/Ttot
re relatively unchanged (Figs. 7 and 8) (Chlif et al., 2007, 2009).owever, few investigations have studied this in detail. Also, theentilatory response to exercise has been reported as normal evenn patients with OHS (Menitove et al., 1984). These findings sug-est that even in clinical patients where central CO2 sensitivitys obviously and dramatically impaired (i.e., OHS patients), thexercise ventilatory response remains within normal limits. Inter-stingly, overweight patients with obstructive sleep apnea areeported to have an elevated ventilatory response (Hargens et al.,
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
009). In contrast to the explanation proposed by the authors,t is unlikely that the exaggerated ventilatory response is dueo changes in chemosensitivity since impaired sensitivity in OHS
ig. 5. Schematic representative of breathing frequency (Fb) vs. ventilation (V • E)elationship in nonobese and obese adults. Figure based on data estimated fromabb et al. (1991).
Fig. 7. Schematic representative of breathing duty cycle (TI/TTot) vs. ventilation(V̇E) relationship in nonobese and obese adults. Figure based on a compilation dataestimated from Salvadori et al. (2008) and Chlif et al. (2007).
patients has no effect on the exercise ventilatory response and thearterial PCO2 changes little from rest to exercise in obese patients.However, this important finding should be studied further giventhe number of overweight and obese men and women with sleepapnea.
ry control during exercise—A brief review. Respir. Physiol. Neurobiol.
In summary, despite increased metabolic demand, increasedwork of breathing, and changes in breathing mechanics, ventilationis mostly within normal limits during exercise due to an increase
Fig. 8. Schematic representative of mean inspiratory flow rate (VT/TI) vs. ventilation(V̇E) relationship in nonobese and obese adults. Figure based on a compilation dataestimated from Salvadori et al. (2008) and Chlif et al. (2007).
espiratory neural drive, which is necessary to generate normalentilation.
. Ventilatory responsiveness at rest in obesity
Unlike exercise, chemosensitivity at rest has been studiedxtensively, yet there are conflicting findings in obesity. Somenvestigations have reported increased (Ge et al., 2005; Narkiewiczt al., 1999), normal (Chapman et al., 1990; Kronenberg et al., 1975;ishibayashi et al., 1987), or decreased (Kunitomo et al., 1988;willich et al., 1975) ventilatory responses to hypercapnia andypoxia in obesity. These differences in responses could be relatedo age bias, differences in mechanical ventilatory limitations, dif-erences in the magnitude of obesity, presence or absence of OHS orbstructive sleep apnea (OSA), and even an increased oxygen cost ofreathing (Crummy et al., 2008; Piper and Grunstein, 2010; Salomet al., 2010). Also, it has been reported that the ventilatory responseo inhaled CO2 can be decreased after marked weight loss due to aeduction in the oxygen cost of breathing and decreased ventilatoryemand (Emirgil and Sobol, 1973). Others may even suggest thathemo-responsiveness has not been measured correctly in manyf these studies (Duffin, 2011; Pedersen et al., 1999). Therefore,here is not a consensus of the effects of obesity on chemosensitiv-ty in otherwise healthy obese adults and further studies are neededsing newer techniques.
As stated earlier, it has been shown in at least one publica-ion that there is an absence of relationship between ventilatoryesponsiveness at rest and the ventilatory response to exercise evenn patients with OHS (Menitove et al., 1984), which is in agree-
ent with conventional thinking in adults (Dempsey et al., 1984).ost investigations of chemosensitivity in obesity are concernedith the responses of patients with OHS, which has growing clin-
cal importance and will be discussed only briefly here. Anotherbservation of interest regarding chemosensitivity in obesity ishe finding that exaggerated respiratory chemosensitivity may bessociated with arterial oxygen saturation at altitude and acuteountain sickness in relatively mildly obese men (Ge et al., 2003,
005). Considering over 60% of the US population is either over-eight or obese and many have easy access to leisure activities at
ltitude, this finding begs further investigation.Only a few studies have estimated respiratory neural drive in
besity during chemosensitivity testing. In a very detailed study,eural respiratory drive (P0.1) was reported to be increased in oth-rwise healthy obese patients during CO2 rebreathing, despite alunted ventilatory response as compared with normal weight con-rols (Sampson and Grassino, 1983b). In contrast, age-, height-,nd weight-matched former OHS patients were reported to haven even more blunted ventilatory response to inhaled CO2 andlso to have a decreased respiratory neural drive (Sampson andrassino, 1983b). It was suggested that both increased neural drivend improved diaphragmatic configuration (i.e., lower FRC), ledo increased neuromuscular drive in the simple obese patients inrder to maintain adequate ventilation in the presence of increasedhest wall load (Sampson and Grassino, 1983b).
In a related study, it has been reported that OHS patients have reduced ventilatory response to CO2 as compared with formerHS patients and simple obese patients (Lopata et al., 1979). Meancclusion pressure after 150 ms was not found to be differentmong OHS, former OHS, or otherwise healthy obese adults buthe variability within groups was quite large and the sample sizesere modest as noted above. Nevertheless, diaphragmatic EMGdi
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
onfirmed these inconsistent findings in this study. In a later papery Lopata and others, it was reported that the ventilatory responseo CO2 rebreathing, while within normal limits in obese patients, itas lower than in nonobese controls, but higher than observed in
PRESSeurobiology xxx (2013) xxx– xxx 5
OSA or OHS patients (Lopata and Onal, 1982). However, P0.15 waswithin normal limits in the otherwise healthy obese subjects andsimilar to nonobese subjects while occlusion pressure was muchlower in obese patients with OSA and OHS during CO2 rebreathing.Mean EMGdi was increased in the obese over that in the nonobesesubjects and the patients with OSA and OHS who had similar values.
The conclusion from these findings was that obese adults havea lower ventilatory responsiveness but an increase in respiratoryneural drive and decrease in neuromuscular coupling efficiency.It appears that in obese adults, respiratory drive can be increasedduring CO2 rebreathing but not enough to completely overcomethe load on the chest wall and thus they have a lower ventilatoryresponse than seen in nonobese controls.
In general, it would appear that obese patients who are unableto activate the respiratory muscles in proportion to chest wall loadsduring CO2 rebreathing (i.e., OHS patients) may be prone to respi-ratory 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 responsiveto CO2 inhalation or CO2 rebreathing, respiratory neural drive willbe increased, but like quiet breathing at rest, ventilation may beincreased, normal, or decreased probably depending on the magni-tude of obesity, the degree of obesity-related effects on respiratoryfunction, the oxygen cost of breathing, respiratory neuromuscularcoupling efficiency, and the load on the chest wall. Patients, who arenot responsive to CO2 inhalation or rebreathing, will probably notincrease respiratory neural drive and will be at the most risk for longterm respiratory failure. However, this is a very complex issue and itis difficult to sort out whether changes in respiratory drive, respira-tory muscle activity, neuromuscular coupling, and ventilation occurin obese adults at rest or during exercise.
6. Summary
A caveat to this review is the limited amount of studies anddata available on ventilatory control during exercise in obesity,OHS, and obese sleep apnea patients. However, exercise train-ing and regular physical activity are major components in thefight of weight balance, gain, and loss. Also, exercise is the largestventilatory challenge to the respiratory system in adults and theexercise ventilatory response remains remarkably normal in simpleand complex obesity. Nevertheless, we know very little about thedetails of exercise ventilatory control in obese patients who havesuch notable changes in metabolic demands, ventilatory require-ments, gas exchange, breathing pattern, and respiratory mechanics.The bottom line is that adaptive ventilatory strategies during exer-cise appear quite impressive in maintaining appropriate ventilatoryhomeostasis in mildly, moderately, and/or extremely otherwisehealthy obese adults.
Acknowledgments
The author wishes to thank Joseph Genovese for his assistance inpreparing the figures and Drs. Vipa Bernhardt and Matthew Spencerfor their editorial comments on the review. This publication wassupported in part by NIH HL-096782, King Charitable FoundationTrust, Susan Lay Atwell Gift for Pulmonary Research, Cain Founda-tion, and Texas Health Presbyterian Hospital Dallas.
References
ry control during exercise—A brief review. Respir. Physiol. Neurobiol.
Babb, T.G., 1997a. Ventilation and respiratory mechanics during exercise in youngersubjects breathing CO2 or HeO2. Respiration Physiology 109, 15–28.
Babb, T.G., 1997b. Ventilatory response to exercise in subjects breathing CO2 orHeO2. Journal of Applied Physiology 82, 746–754.
abb, T.G., 1999. Mechanical ventilatory constraints in aging, lung disease, and obe-sity: perspectives and brief review. Medicine and Science in Sports and Exercise31, S12–S22.
abb, T.G., Buskirk, E.R., Hodgson, J.L., 1989. Exercise end-expiratory lung volumes inlean and moderately obese women. International Journal of Obesity 13, 11–19.
abb, T.G., Korzick, D., Meador, M., Hodgson, J.L., Buskirk, E.R., 1991. Ventilatoryresponse of moderately obese women to submaximal exercise. InternationalJournal of Obesity 15, 59–65.
abb, T.G., DeLorey, D.S., Wyrick, B.L., Gardner, P.P., 2002. Mild obesity does not limitchange in end-expiratory lung volume during cycling in young women. Journalof Applied Physiology 92, 2483–2490.
abb, T.G., DeLorey, D.S., Wyrick, B.L., 2003. Ventilatory response to exercise inaged runners breathing He–O2 or inspired CO2. Journal of Applied Physiology94, 685–693.
abb, T.G., Ranasinghe, K.G., Comeau, L.A., Semon, T.L., Schwartz, B., 2008. Dys-pnea on exertion in obese women: association with an increased oxygen cost ofbreathing. American Journal of Respiratory Critical Care Medicine 178, 116–123.
abb, T.G., Wood, H.E., Mitchell, G.S., 2010. Short- and long-term modulation of theexercise ventilatory response. Medicine and Science in Sports and Exercise 42,1681–1687.
abb, T.G., Wyrick, B.L., Chase, P.J., DeLorey, D.S., Rodder, S.G., Feng, M.Y., Ranas-inghe, K.G., 2011. Weight loss via diet and exercise improves exercise breathingmechanics in obese men. Chest 140, 454–460.
ach, K.B., Lutcavage, M.E., Mitchell, G.S., 1993. Serotonin is necessary for short-term modulation of the exercise ventilatory response. Respiration Physiology91, 57–70.
ennett, F.M., Fordyce, W.E., 1985. Characteristics of the ventilatory exercise stim-ulus. Respiration Physiology 59, 55–63.
accurately estimates arterial PCO2 at rest and during exercise in morbidly obeseadults. Chest 143, 471–477.
rown, L.K., Schwartz, J., Miller, A.M., Pilipski, M., Teirstein, A.S., 1990. Respira-tory drive and pattern during inertially-loaded CO2 rebreathing: implications formodels of respiratory mechanics in obesity. Respiration Physiology 80, 231–243.
urki, N.K., Baker, R.W., 1984. Ventilatory regulation in eucapnic morbid obesity.American Review of Respiratory Disease 129, 538–543.
asaburi, R., 2012. The mechanism of the exercise hyperpnea: the ultrasecret revis-ited. American Journal of Respiratory Critical Care Medicine 186, 578–579.
hapman, K.R., Himal, H.S., Rebuck, A.S., 1990. Ventilatory responses to hypercapniaand hypoxia in patients with eucapnic morbid obesity before and after weightloss. Clinical Science (London) 78, 541–545.
hlif, M., Keochkerian, D., Feki, Y., Vaidie, A., Choquet, D., Ahmaidi, S., 2007. Inspi-ratory muscle activity during incremental exercise in obese men. InternationalJournal of Obesity (London) 31, 1456–1463.
hlif, M., Keochkerian, D., Choquet, D., Vaidie, A., Ahmaidi, S., 2009. Effects of obe-sity on breathing pattern ventilatory neural drive and mechanics. RespiratoryPhysiology & Neurobiology 168, 198–202.
rummy, F., Naughton, M.T., Elborn, J.S., 2008. Obesity and the respiratory physician.Thorax 63, 576–577.
eLorey, D.S., Wyrick, B.L., Babb, T.G., 2005. Mild-to-moderate obesity: implicationsfor respiratory mechanics at rest and during exercise in young men. Interna-tional Journal of Obesity 29, 1039–1047.
empsey, J.A., Reddan, W., Balke, B., Rankin, J., 1966a. Work capacity determinantsand physiologic cost of weight-supported work in obesity. Journal of AppliedPhysiology 21, 1815–1820.
empsey, J.A., Reddan, W., Rankin, J., Balke, B., 1966b. Alveolar-arterial gas exchangeduring muscular work in obesity. Journal of Applied Physiology 21, 1807–1814.
empsey, J.A., Mitchell, G.S., Smith, C.A., 1984. Exercise and chemoreception. Amer-ican Review of Respiratory Disease 129, S31–S34.
reher, M., Kabitz, H.J., Burgardt, V., Walterspacher, S., Windisch, W., 2010. Pro-portional assist ventilation improves exercise capacity in patients with obesity.Respiration 80, 106–111.
uffin, J., 2011. Measuring the respiratory chemoreflexes in humans. RespiratoryPhysiology & Neurobiology 177, 71–79.
ldridge, F.L., 1994. Central integration of mechanisms in exercise hyperpnea.Medicine and Science in Sports and Exercise 26, 319–327.
mirgil, C., Sobol, B.J., 1973. The effects of weight reduction on pulmonary func-tion and the sensitivity of the respiratory center in obesity. American Review ofRespiratory Disease 108, 831–842.
orster, H.V., 2000. Exercise hyperpnea: where do we go from here? Exercise andSport Sciences Reviews 28, 133–137.
orster, H.V., Dunning, M.B., Lowry, T.F., Erickson, B.K., Forster, M.A., Pan, L.G., Brice,A.G., Effros, R.M., 1993. Effect of asthma and ventilatory loading on arterialPCO2 of humans during submaximal exercise. Journal of Applied Physiology 75,1385–1394.
e, R.L., Chase, P.J., Witkowski, S., Wyrick, B.L., Stone, J., Levine, B.D., Babb, T.G., 2003.Obesity associations with acute mountain sickness. Annals of Internal Medicine139, 253–257.
e, R.L., Stone, J.A., Levine, B.D., Babb, T.G., 2005. Exaggerated respiratory chemosen-sitivity and association with SaO2 level at 3568 m in obesity. RespiratoryPhysiology & Neurobiology 146, 47–54.
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
argens, T.A., Guill, S.G., Aron, A., Zedalis, D., Gregg, J.M., Nickols-Richardson, S.M.,Herbert, W.G., 2009. Altered ventilatory responses to exercise testing in youngadult men with obstructive sleep apnea. Respiratory Medicine 103, 1063–1069.
ouk, J.C., 1988. Control strategies in physiological systems. FASEB Journal 2,97–107.
PRESSeurobiology xxx (2013) xxx– xxx
Kronenberg, R.S., Gabel, R.A., Severinghaus, J.W., 1975. Normal chemoreceptor func-tion in obesity before and after ileal bypass surgery to force weight reduction.American Journal of Medicine 59, 349–353.
Kunitomo, F., Kimura, H., Tatsumi, K., Kuriyama, T., Watanabe, S., Honda, Y., 1988.Sex differences in awake ventilatory drive and abnormal breathing during sleepin eucapnic obesity. Chest 93, 968–976.
Lopata, M., Onal, E., 1982. Mass loading sleep apnea, and the pathogenesis of obesityhypoventilation. American Review of Respiratory Disease 126, 640–645.
Lopata, M., Freilich, R.A., Onal, E., Pearle, J., Lourenco, R.V., 1979. Ventilatory con-trol and the obesity hypoventilation syndrome. American Review of RespiratoryDisease 119, 165–168.
Lourenco, R.V., 1969. Diaphragm activity in obesity. Journal of Clinical Investigation48, 1609–1614.
Luce, J.M., 1980. Respiratory complications of obesity. Chest 78, 626–631 (review).Luo, Y.M., Moxham, J., 2005. Measurement of neural respiratory drive in patients
with COPD. Respiratory Physiology & Neurobiology 146, 165–174.Martin, P.A., Mitchell, G.S., 1993. Long-term modulation of the exercise ventilatory
response in goats. Journal of Physiology 470, 601–617.McIlroy, M.B., 1959. Dyspnea and the work of breathing in diseases of the heart and
lungs. Progress in Cardiovascular Diseases 1, 284–297.Menitove, S.M., Rapoport, D.M., Epstein, H., Sorkin, B., Goldring, R.M., 1984. CO2
rebreathing and exercise ventilatory responses in humans. Journal of AppliedPhysiology 56, 1039–1044.
Milic-Emili, G., Petit, J.M., Deroanne, R., 1960. The effects of respiratory rate on themechanical work of breathing during muscular exercise. International Z Angewof Physiology 18, 330–340.
Mitchell, G.S., 1990. Ventilatory control during exercise with increased respiratorydead space in goats. Journal of Applied Physiology 69, 718–727.
Mitchell, G.S., Babb, T.G., 2006. Layers of exercise hyperpnea: modulation and plas-ticity. Respiratory Physiology & Neurobiology 151, 251–266.
Mitchell, G.S., Johnson, S.M., 2003. Plasticity in respiratory motor control: invitedreview: neuroplasticity in respiratory motor control. Journal of Applied Physi-ology 94, 358–374.
Mitchell, G.S., Smith, C.A., Dempsey, J.A., 1984. Changes in the VI–V CO2 relationshipduring exercise in goats: role of carotid bodies. Journal of Applied Physiology 57,1894–1900.
Mitchell, G.S., Bach, K.B., Martin, P.A., Foley, K.T., 1993. Modulation and plasticityof the exercise ventilatory response. Funktionsanalyse biologischer Systeme 23,269–277.
Narkiewicz, K., Kato, M., Pesek, C.A., Somers, V.K., 1999. Human obesity is character-ized by a selective potentiation of central chemoreflex sensitivity. Hypertension33, 1153–1158.
Nishibayashi, Y., Kimura, H., Maruyama, R., Ohyabu, Y., Masuyama, H., Honda, Y.,1987. Differences in ventilatory responses to hypoxia and hypercapnia betweennormal and judo athletes with moderate obesity. European Journal of AppliedPhysiology 56, 144–150.
Ofir, D., Laveneziana, P., Webb, K.A., O‘Donnell, D.E., 2007. Ventilatory and percep-tual responses to cycle exercise in obese women. Journal of Applied Physiology102, 2217–2226.
Parameswaran, K., Todd, D.C., Soth, M., 2006. Altered respiratory physiology inobesity. Canadian Respiratory Journal 13, 203–210.
Pedersen, M.E., Fatemian, M., Robbins, P.A., 1999. Identification of fast and slowventilatory responses to carbon dioxide under hypoxic and hyperoxic conditionsin humans. Journal of Physiology 521 (Pt. 1), 273–287.
Piper, A.J., Grunstein, R.R., 2010. Big breathing: the complex interaction of obe-sity, hypoventilation, weight loss, and respiratory function. Journal of AppliedPhysiology 108, 199–205.
Poon, C.S., 1992. Potentiation of exercise ventilatory response by airway CO2 anddead space loading. Journal of Applied Physiology 73, 591–595.
Romagnoli, I., Laveneziana, P., Clini, E.M., Palange, P., Valli, G., de Blasio, F., Gigliotti,F., Scano, G., 2008. Role of hyperinflation vs. deflation on dyspnoea in severelyto extremely obese subjects. Acta Physiology (Oxford) 193, 393–402.
Salome, C.M., King, G.G., Berend, N., 2010. Physiology of obesity and effects on lungfunction. Journal of Applied Physiology 108, 206–211.
Salvadori, A., Fanari, P., Tovaglieri, I., Giacomotti, E., Nibbio, F., Belardi, F., Longhini,E., 2008. Ventilation and its control during incremental exercise in obesity.Respiration 75, 26–33.
Sampson, M.G., Grassino, A.E., 1983a. Load compensation in obese patients duringquiet tidal breathing. Journal of Applied Physiology 55, 1269–1276.
Sampson, M.G., Grassino, K., 1983b. Neuromechanical properties in obese patientsduring carbon dioxide rebreathing. American Journal of Medicine 75, 81–90.
Steier, J., Jolley, C.J., Seymour, J., Roughton, M., Polkey, M.I., Moxham, J., 2009. Neuralrespiratory drive in obesity. Thorax 64, 719–725.
Sun, X.G., Hansen, J.E., Garatachea, N., Storer, T.W., Wasserman, K., 2002. Ventilatoryefficiency during exercise in healthy subjects. American Journal of Respiratoryand Critical Care Medicine 166, 1443–1448.
Turner, D., Stewart, J.D., 2004. Associative conditioning with leg cycling and inspi-ratory resistance enhances the early exercise ventilatory response in humans.European Journal of Applied Physiology 93, 333–339.
Turner, D.L., Bach, K.B., Martin, P.A., Olsen, E.B., Brownfield, M., Foley, K.T., Mitchell,G.S., 1997. Modulation of ventilatory control during exercise. Respiration Phys-
ry control during exercise—A brief review. Respir. Physiol. Neurobiol.
iology 110, 277–285.Wang, L.Y., Cerny, F.J., 2004. Ventilatory response to exercise in simulated obesity
by chest loading. Medicine and Science in Sports and Exercise’s 36, 780–786.Wasserman, K., Whipp, B.J., 1975. Exercise physiology in health and disease. Amer-
ood, H.E., Fatemian, M., Robbins, P.A., 2003. A learned component ofthe ventilatory response to exercise in man. Journal of Physiology 553,967–974.
ood, H.E., Mitchell, G.S., Babb, T.G., 2008a. Short-term modulation of the exer-cise ventilatory response in young men. Journal of Applied Physiology 104,
Please cite this article in press as: Babb, T.G., Obesity: Challenges to ventilato(2013), http://dx.doi.org/10.1016/j.resp.2013.05.019
Babb, T.G., 2008b. The ventilatory response to exercise does not differ betweenobese women with and without dyspnea on exertion. Advances in ExperimentalMedicine and Biology 605, 514–518.
PRESSeurobiology xxx (2013) xxx– xxx 7
Wood, H.E., Mitchell, G.S., Babb, T.G., 2010. Short-term modulation of the exerciseventilatory response in older men. Respiratory Physiology & Neurobiology 173,37–46.
Wood, H.E., Mitchell, G.S., Babb, T.G., 2011. Short-term modulation of the exerciseventilatory response in younger and older women. Respiratory Physiology &Neurobiology 179, 235–247.
Zavorsky, G.S., Hoffman, S.L., 2008. Pulmonary gas exchange in the morbidly obese.Obesity Reviews 9, 326–339.
