Abstract
Obesity hypoventilation syndrome describes the association between obesity and the development of chronic daytime alveolar hypoventilation. This syndrome arises from a complex interaction between sleep-disordered breathing, diminished respiratory drive, and obesity-related respiratory impairment, and is associated with significant morbidity and mortality. Therapy directed toward reversing these abnormalities leads to improved daytime breathing, with available treatment options including positive pressure therapy, weight loss, and pharmacological management. However, a lack of large-scale, well-designed studies evaluating these various therapies has limited the development of evidence-based treatment recommendations. Although treatment directed toward improving sleep-disordered breathing is usually effective, not all patients tolerate mask ventilation and awake hypercapnia may persist despite effective use. In the longer term, weight loss is desirable, but data on the success and sustainability of this approach in obesity hypoventilation are lacking. The review outlines the major mechanisms believed to underlie the development of hypoventilation in this subgroup of obese patients, their clinical presentation, and current therapy options.
Obesity is a major public health issue, and despite the increasing attention this disorder has received over the past decade, not only are obesity rates continuing to increase but also we are seeing the emergence of an increasing number of individuals who can be categorized as super obese (body mass index [BMI] > 50 kg/m2) (1). As weight increases, so do the health consequences, including those related to the respiratory system. Obesity hypoventilation syndrome (OHS) refers to the appearance of awake hypercapnia (PaCO2 > 45 mm Hg) in the obese patient (BMI > 30 kg/m2) after other causes that could account for awake hypoventilation, such as lung or neuromuscular disease, have been excluded. Although sleep-disordered breathing is not currently part of the basic definition of OHS, breathing during sleep in these individuals typically encompasses a number of polysomnographic defined phenotypes, including repetitive frank obstructive sleep apnea (OSAS) with hypercapnia, flow limitation causing obstructive hypoventilation, through to hypoventilation in all sleep stages (2). Sleep hypoventilation alone does not define OHS unless daytime hypercapnia is also present. However, it is possible that obese patients with hypoventilation during sleep without awake hypercapnia have a “prodromal” form of OHS and will later develop chronic hypercapnia. This may be similar to the clinical scenario observed in patients with sleep-disordered breathing and neuromuscular disease (3).
The incidence of OHS increases significantly as obesity increases, with a reported prevalence of around 10 to 20% in outpatients presenting to sleep clinics (4–6) to almost 50% of hospitalized patients with a BMI greater than 50 kg/m2 (7). Current estimates suggest that around 0.3 to 0.4% of the population may have OHS (8, 9). However, the accuracy of prevalence data has been limited by inclusion of multiple small studies, failure to exclude some patients with chronic obstructive pulmonary disease, and variable definitions of obstructive sleep apnea (8). There are no prospective observational cohort studies investigating which patients with OSA will develop OHS with weight gain. Nevertheless, it is reasonable to assume there are several hundred thousand individuals in the United States with OHS. In this review, we highlight the pathophysiology that determines which patients with obesity develop awake hypoventilation and the clinical impact of OHS. Recent data on management approaches are also discussed. The review emphasizes the importance of early detection and intervention in patients with OHS, considering the substantial morbidity and mortality associated with this disorder.
One of the more intriguing aspects of the interaction of respiratory function and obesity is that only some morbidly obese patients develop awake hypoventilation. There are clearly specific differences between obese individuals who maintain normal ventilation awake and asleep, those who develop sleep-disordered breathing with normal daytime ventilation, and those who exhibit awake hypercapnia in the absence of lung or neuromuscular disease. These interindividual differences are complex, reflecting the diverse impact of obesity on breathing (10).
Obesity, particularly when it is severe, is associated with significant changes in pulmonary mechanics and respiratory muscle performance. However, many of these effects are magnified in those obese patients who develop OHS compared with equally obese individuals either with or without sleep-disordered breathing (Table 1) (11). Breathing at abnormally low lung volumes reduces chest wall and respiratory system compliance (12, 13) and increases airway resistance (14). When expiratory reserve volume is low, small airway closure and air trapping occur, resulting in expiratory flow limitation and the development of intrinsic positive end-expiratory pressure (15). These changes are more marked in the supine position and contribute to the increased work of breathing by imposing a threshold load on the inspiratory muscles (15, 16). It is not known whether the development of intrinsic positive end-expiratory pressure is greater in patients with OHS compared with equally obese eucapnic individuals. However, it has been shown that the work of breathing in sitting and supine (awake or in stage II sleep) positions is significantly higher in patients with OHS compared with similarly obese eucapnic patients (17).
Obesity Hypoventilation | Eucapnic Morbid Obesity | References | |
|---|---|---|---|
| FEV1/FVC | Normal | Normal | 4, 7, 8, 10, 11, 18, 22, 62 |
| Total lung capacity | Slightly reduced | Normal | 4, 8, 11, 30, 31, 59, 62 |
| Functional residual capacity | Reduced | Reduced | 10, 13, 15, 31 |
| Vital capacity | Markedly reduced | Normal/reduced | 4, 5, 8, 16, 17, 30 |
| Expiratory reserve volume | Markedly reduced | Reduced | 15, 30, 62 |
| Respiratory system compliance | Markedly reduced | Reduced | 12, 16 |
| Work of breathing | Significantly increased | Increased | 16, 17 |
| Respiratory drive | Normal | Increased | 16, 29–31 |
| Inspiratory muscle strength | Reduced | Normal | 16, 30 |
| Ventilatory response to CO2 | Normal/reduced | Normal/increased | 18, 30, 32, 33, 35 |
| PaCO2 | Increased/markedly increased | Normal | 6, 7, 11, 16, 17, 31–33, 52 |
| Serum bicarbonate | Increased | Normal | 6, 7, 16, 31, 33 |
| Leptin | Markedly increased | Increased | 38 |
There are several mechanisms to potentially explain the greater impairment of respiratory function in OHS. First, in those with more severe OHS, respiratory muscle performance may be affected by the biochemical disturbance associated with hypoventilation (acidosis and hypoxemia). Whether a primary myopathic process also exists is currently unknown, as detailed muscle structural analysis has not been performed in individuals with OHS. Second, patients with OHS have a higher degree of central fat distribution, as demonstrated by larger neck circumferences and higher waist:hip ratios compared with eucapnic obese patients or patients with OSAS (11, 18). Central adiposity results in cephalic displacement of the diaphragm. This produces inefficient mechanical performance (19), which worsens when the individual is lying supine. In addition, centrally distributed weight reduces lung volumes to a much greater degree than weight deposited peripherally (20). This would contribute to greater reductions in lung volumes and more marked mechanical ventilatory constraints, which would increase the work of breathing while reducing respiratory muscle efficiency in patients with OHS. The distribution of excess weight is also important in gas exchange with centrally obese individuals, regardless of sex or BMI, exhibiting poorer gas exchange (21).
Despite the clear differences between OHS and eucapnic obese patients with respect to respiratory function, there are obviously other factors that influence the emergence of awake hypoventilation, including sleep-disordered breathing.
There is a strong consensus that most patients with OHS have underlying upper airway obstruction (2, 4, 10, 22). Patients typically report a past history of snoring and witnessed apneas, and approximately 90% demonstrate upper airway obstruction on polysomnogram (4). Daytime symptomatology in OHS, such as daytime sleepiness and poor concentration, is similar to that reported in OSAS. In many instances, OHS will respond to relief of upper airway obstruction by nasal continuous positive airway pressure (CPAP). A significant proportion of patients with OHS diagnosed initially with sleep hypoventilation alone will later exhibit OSA if withdrawn from noninvasive ventilation (23). However, there are no large longitudinal studies that inform on the development of OHS over time, and therefore it is difficult to exclude the possibility that some patients can develop OHS in the absence of upper airway dysfunction at some time in the evolution of the disorder. The apnea-hypopnea index has been shown in some studies to be an independent risk factor for the development of hypercapnia (6, 8). However, the issue is likely to be more complex than the frequency of events occurring during sleep. Other authors have highlighted the importance of the duration of disordered breathing events relative to the interapnea period in the development of hypercapnia in patients with obesity and OSA. When periods of abnormal breathing are long and the time to restore ventilation is short and/or respiratory efforts are reduced during the recovery period, acute increases in CO2 can occur (24).
Recently, a model has been proposed that links this transient retention of CO2 during apneic events in sleep with the development of chronic awake hypercapnia (25). A key feature of this model includes the eventual increase in renal bicarbonate concentration to buffer these acute overnight increases in CO2. In turn, this results in depression of ventilatory responsiveness to CO2 during wakefulness, eventually promoting daytime hypoventilation (Figure 1). The greater ventilatory limitations imposed by more extreme central obesity and/or the development of decreased central respiratory drive may initiate the acute failure to compensate for sleep-disordered breathing. However, for awake CO2 to emerge, the renal compensatory mechanism must also be compromised (25). Because the presence of these risk factors can vary considerably between similarly obese patients with OSAS, this model helps to explain why only a subgroup of these individuals develop awake hypercapnia.
Figure 1. Outline of some of the interactions between factors believed to be contributing to the development of hypercapnia in patients with severe obesity. The (+) sign denotes this factor, if normal or increased, has a positive influence on maintaining ventilation. The (−) sign denotes factors that, if reduced or blunted, would contribute to lowered ventilation and eventual hypercapnia. HCVR = hypercapnic ventilatory response. Reprinted by permission from Reference 10.
[More] [Minimize]Sustained hypoxemia in the absence of obvious upper airway dysfunction will also occur, and the proportion of sleep time spent less than 90% (% total sleep time oxygen saturation as measured by pulse oximetry [SpO2] < 90%) has been shown to be strongly associated with the development of awake hypercapnia (8). Although it is not clear from individual studies whether hypoxia was the cause or consequence of hypercapnia, it is possible that hypoxia could interfere with the synthesis of a number of neurotransmitters involved in central respiratory control (26, 27). Although not yet studied in OHS, sustained hypoxia during sleep delays arousal in response to resistive loading in healthy nonobese males (28) and could contribute to worsening sleep hypoventilation and CO2 retention.
Alterations in central respiratory drive also underpin which obese patient with or without OSAS will develop daytime hypercapnia. Normally, severe obesity is associated with increased respiratory drive, which assists in maintaining eucapnia despite abnormal chest wall mechanics and high work of breathing (16, 29, 30). Those with OHS do not display this augmented drive (30, 31). In addition, ventilatory responsiveness to hypoxia and hypercapnia is diminished (32–34) and does not appear to have a familial basis (35, 36). Rather, this seems to be an acquired phenomenon, with recent work highlighting the potential role of hormones or adipokines in this process.
Leptin is a circulating protein produced mainly by adipose tissue (adipokine) that interacts with hypothalamic receptors to inhibit eating. The leptin-deficient ob/ob mouse model has provided some insight into potential mechanisms of OHS. Compared with wild-type mice and other obese mouse models, ob/ob mice do not produce functioning leptin and exhibit features of OHS with impaired respiratory mechanics, depressed ventilatory responsiveness, and awake hypercapnia. They also have marked reductions in lung volumes, pulmonary compliance, and abnormal respiratory muscle function (37). Leptin replacement in these mice reverses their OHS, and in this way, leptin can be considered a respiratory stimulant.
In humans, leptin deficiency in obesity is extremely rare, and instead, similar to obesity in wild-type mice, there is a variable elevation in circulating leptin. Clearly, if these high leptin levels were biologically active there would be reduced eating and subsequently weight loss. This is obviously not the case in human obesity, and the problem instead is “leptin resistance.” This may play a role in human obesity-related breathing disorders, such as OHS or OSA. Therefore, the development of a resistance to leptin, or perhaps more correctly a “central leptin deficiency,” could contribute to the development of awake hypoventilation by altering respiratory drive output as well, affecting the mechanical properties of the lungs and chest wall, attenuating the normal compensatory mechanisms used by individuals to cope with obesity-related respiratory loads.
Plasma leptin levels are higher in OSAS or OHS compared with weight-matched control subjects without sleep-disordered breathing (38, 39). Importantly, leptin levels are a better predictor of hypercapnia than degree of adiposity (38). Higher serum leptin concentrations are also associated with both a reduced respiratory drive and a reduced response to hypercapnia in severely obese individuals (40). Until recently, the concept of using leptin to treat human obesity (and possibly OHS) has been limited by leptin resistance. New data on possible ways of overcoming leptin resistance and emerging clinical trials suggest that in the future using recombinant leptin to reverse OHS may be possible (41).
Other hormonal mechanisms may also be operative in OHS. Growth hormone increases ventilatory responsiveness (42). Lower 24-hour growth hormone levels, as indicated by lower insulin-like growth factor I (IGF-I) levels, have been observed in OHS, with a strong negative correlation between IGF-I and both PaCO2 and bicarbonate reported (33). However, the effect of recombinant growth hormone on OHS is unknown.
Patients with OHS exhibit lower daytime PaO2 and higher PaCO2 compared with those with morbid obesity or OSAS and thus spend a greater proportion of sleep time with SpO2 < 90% (4, 11, 43). In turn, this will result in more frequent presentation with peripheral edema, pulmonary hypertension, and cor pulmonale (4, 44). Patients with OHS are also more likely to report moderate to severe dyspnea compared with eucapnic patients with OSAS (45). However, clinical presentation in OHS may be identical to patients with OSAS. Consequently, the diagnosis can be overlooked not only in a sleep clinic population of patients with chronic stable disease but even during hospitalization for an acute illness (7, 46). Hospitalization rates and ongoing use of health care service requirements are significantly higher among patients with OHS compared with morbidly obese eucapnic patients (47). Despite this high contact with health care providers, there appears to be a significant delay in the diagnosis of this disorder and the institution of definitive therapy unless referral to a respiratory or sleep physician is made (7, 45, 46).
Although large-scale longitudinal observation data are not available in untreated OHS, patients with this condition are more likely than eucapnic obese patients to require admission to intensive care if hospitalized and are more likely to need invasive ventilation (7). Furthermore, 18 months after hospital discharge, mortality was 23% in a group of patients with OHS compared with 9% in those with uncomplicated obesity (7). In another study evaluating long term noninvasive ventilation, almost half those who refused therapy (7/15) had died within the follow-up period of 50 ± 25 months compared with 3 of 54 patients managed with positive pressure therapy (44).
In addition to morbidity and mortality related to respiratory complications, patients with OHS also exhibit greater cardiometabolic morbidity compared with those with OSAS or simple severe obesity. Rates of systemic hypertension, congestive heart failure, cor pulmonale, and angina are higher among patients with OHS compared with those with eucapnic obesity (47, 48). Patients with OHS are also characterized by higher insulin resistance and more frequently are treated by glucose-lowering medications (18). Given the known interaction of OSA, obesity, and cardiometabolic disease, these findings in OHS are not surprising (49, 50). In a recent prospective controlled study, an increase in the proatherogenic chemokine regulated on activation, normal T-cell expressed and secreted, lower levels of the antiatherogenic adipokine adiponectin, and impaired endothelial function were seen in patients with OHS compared with age- and BMI-matched eucapnic control subjects (18). The presence of high inflammatory markers before and after treatment for sleep-disordered breathing in OHS has also been shown to be a factor associated with poor prognosis in this population (51).
Symptoms and lifestyle limitations caused by the respiratory and obesity aspects of OHS have a significant effect on quality of life (22, 52, 53). These patients experience significant dyspnea (44, 45) and daytime sleepiness (52), which can impact on both the physical and mental/social aspects of quality of life (53). Despite improving gas exchange during sleep and wakefulness with treatment, many individuals still report low quality-of-life scores, which may reflect the ongoing impact of comorbidities present in severe obesity (22). In contrast, in a group of less obese Japanese patients with OHS (mean BMI 36 ± 9 kg/m2), improvements in all domains of the SF-36, apart from bodily pain, occurred after 3 to 6 months of CPAP therapy, with post-treatment scores similar to those reported by nonobese and healthy subjects (52). Improving quality of life is an important aspect of intervention in patients with chronic hypoventilation, including OHS, as there appears to be an association between health-related quality of life and mortality (54).
At present no classification system for severity of OHS has been established and generally accepted. However, various characteristics of the disorder have been suggested by which severity could be graded, including the degree of awake respiratory failure, BMI, complications related to OHS, or even the response to initial CPAP therapy (55). The clinical heterogeneity of OHS highlights the need for specific characterization of patient cohorts to better understand the mechanisms underlying this disorder and how this may influence the response to different therapies (56).
To diagnose OHS, an increased awake PaCO2 is required. However, because arterial blood gases are not routinely performed in sleep clinics and laboratories, and chronic presentation may be similar to uncomplicated OSAS, the disorder can be overlooked unless clinicians have a high index of suspicion. Recently published medical guidelines for patients undergoing bariatric surgery have recognized this issue and recommend that formal respiratory evaluation, including arterial blood gases, be performed as part of the preoperative assessment in those individuals with disordered sleep as well as those with super (BMI > 50) obesity (57). Despite such guidelines, there are no data on the most appropriate cost-effective clinical screening pathway for detection of OHS in patient populations.
Simple measures, such as pulse oximetry and serum bicarbonate, can be readily performed in clinics and serve as useful screening tools to identify potential candidates with OHS. A serum bicarbonate 27 mEq/L or greater has been shown to be highly sensitive (92%) although not specific (50%) for the presence of an increased CO2, and therefore clinically a helpful procedure for screening (6). Similarly, PaO2 is generally less than 70 mm Hg in OHS, particularly in those with more severe disease (11, 43). Therefore, a pulse oximetry reading of less than 94% would suggest the need for an arterial blood gas measurement to clarify the diagnosis (6).
Given the cost and limited facilities for performing full polysomnography in many countries, there is increasing use of simplified respiratory monitoring and autotitrating pressure devices for the diagnosis and treatment of OSAS. Although current clinical guidelines advise against the unattended titration of CPAP in OHS (58), it is likely that a proportion of individuals will be managed in this way simply because the disorder is not recognized. Although CPAP may be effective in some patients (2, 22, 43), sustained nocturnal desaturation and hypoventilation may persist in others, resulting in an incomplete or worsening response to therapy (43, 59). Consequently, it is important to identify patients with OHS before a CPAP titration study.
Although monitoring CO2 during sleep using transcutaneous CO2 is not widely deployed in most clinical centers, the technique can be of value in documenting the degree to which CO2 is retained, especially during REM sleep. In this way it may be a useful technique to detect prodromal OHS in obese patients. It has also been used in severely obese patients during positive airway pressure (PAP) therapy, demonstrating good agreement with PaCO2 measured from arterial blood sampling (60), although careful calibration is required to ensure accuracy of measurements. Nevertheless, there is a lack of evidence from randomized controlled trials to determine whether the diagnosis and management of patients with OHS using continuous transcutaneous monitoring of CO2 offers any clinical benefits over oxygen saturation and awake arterial blood gases measurements alone.
Current treatment approaches for OHS can be broadly classed into two areas: medical therapies, including PAP therapy designed to treat sleep-disordered breathing and improve nocturnal gas exchange, and surgical intervention to promote and maintain weight loss.
Reversal of daytime CO2 can be achieved with CPAP therapy alone when chronic hypercapnia is largely a consequence of upper airway obstruction (2, 22, 43). Flow limitation producing sustained periods of hypoventilation can also occur and again will respond to CPAP therapy if sufficient pressure levels are applied (2). In the majority of cases, titration of CPAP will be the first approach to treatment (22, 61), with the goal of normalizing oxygen saturation and preventing increases in nocturnal CO2 levels. Pressure is titrated upward to eliminate apneas, hypopneas, and snoring and to stabilize oxygen saturation, with a switch to bilevel therapy if sustained desaturation and elevated CO2 levels persist. During bilevel therapy, the level of airway pressure delivered during inspiration (IPAP) and expiration (EPAP) can be adjusted separately, with EPAP increased to eliminate obstructive events while IPAP is increased above the EPAP level to improve alveolar ventilation. A pressure difference between IPAP and EPAP of at least 6 to 7cm H2O is generally required (44, 48, 62). In many published studies, the move to bilevel therapy is undertaken within the first night of PAP titration if SpO2 of 90% or greater is not achieved despite the elimination of obstructive events. Based on this approach, previous reports have suggested that around 20 to 50% of patients with OHS will fail CPAP and require longer-term management with bilevel therapy (2, 43, 61). However, in a small study of patients with OHS randomized to either CPAP or bilevel therapy for a 3-month period, no between-group differences in awake CO2, compliance with therapy, or daytime sleepiness were found. This lack of difference was observed even though 11 of the 18 patients randomized to CPAP therapy continued to exhibit sustained oxygen desaturation between 80 and 88% during the first night of titration (22). Furthermore, after 3 months of therapy, only four of these patients continued to desaturate during sleep despite control of the upper airway, suggesting that a complete initial response to CPAP therapy may not be necessary for longer-term resolution of sleep and daytime hypoventilation. Other work has shown that better adherence with PAP therapy plays an important role in the improvement in CO2 achieved in hypercapnic patients with OSAS, irrespective of whether CPAP or bilevel therapy is used (61). After an initial period of bilevel support, some individuals can be effectively managed with CPAP alone (22, 23, 44, 63). Longer-term data will be required to provide treatment algorithms that explain which patients can be initially managed with CPAP from the outset or switched to this therapy after a period of bilevel ventilation. Longer-term outcomes would need to include quality of life, compliance, relapse, or even mortality.
Longer-term observational studies of bilevel therapy have consistently reported improved awake blood gases, daytime sleepiness, and ventilatory responsiveness to CO2, fewer hospitalizations, and better quality of life compared with baseline measures (47, 53). However, there is only limited evidence from randomized trials comparing clinical outcomes between different treatment modalities (22, 59, 64). Limitations of these trials include the small number of patients studied (10–36 patients), the short-term nature of follow-up (single night to 3 mo), and comparisons only performed between different types of PAP (CPAP and bilevel, or bilevel with and without average volume–assured pressure support ventilation), in groups with relatively mild OHS based on daytime CO2 levels. The extent to which the findings of these small randomized trials can be applied to the broader OHS population requires confirmation in larger multicenter studies. Several studies have reported higher discontinuation rates among females compared with males with OHS (44, 48), although the reasons for this are unclear. Given the significantly higher mortality rate reported for patients with untreated OHS compared with those continuing on therapy (7, 44), identifying causes and ensuring alternate therapy options are offered to noncompliant PAP patients is important.
A substantial number of patients may require oxygen therapy in addition to PAP initially to maintain SpO2 greater than 90% (22, 44, 61), but once effective nocturnal ventilation is established, this need decreases significantly. However, suboptimal oxygenation (defined by percentage of recording time with SpO2 < 90%) both during wakefulness and sleep can be present in some individuals despite improved daytime blood gases, and although this did not translate into greater dyspnea or daytime sleepiness in one study (63), daytime hypoxemia both before and persisting after the initiation of PAP therapy has been shown to be an independent predictor of poor survival in OHS (51). To date, outcomes research in OHS has been limited by lack of agreement on endpoints of therapy. We do not really know what constitutes a normal awake PCO2 level in these patients or what represents an acceptable or safe level of oxygen desaturation level during sleep. One important future research agenda is to define and provide evidence supporting treatment goals in patients with OHS.
Even when patients are adherent to PAP therapy, up to 25% may remain hypercapnic with an awake CO2 greater than 45 mm Hg. This needs to be qualified, because adherence is frequently defined as more than 4 or 4.5 hours of PAP therapy during sleep (61). Given that the average sleep length in most individuals is at least 6 to 7 hours per night, some adherent patients will be exposed to residual hypoventilation, and therefore incomplete reversal of awake hypercapnia may occur. In cases in which severe daytime gas exchange abnormalities persist, or the patient is intolerant of mask PAP therapy, alternate treatment options need to be considered.
A reduction in nocturnal obstructive events and normalization of awake CO2 can be achieved in some patients with severe OHS after undergoing a tracheostomy (65, 66). However, daytime hypoventilation may persist (65, 66), whereas in others external blockage of the tracheostomy by excess adipose tissue around the neck can also occur (67). Therefore, although a tracheostomy may be needed in a small subset of patients with OHS who are intolerant of mask PAP therapy and who exhibit life-threatening complications, it may not be a viable long-term option for therapy.
Early case studies reported significant improvements in lung function, central respiratory drive, and daytime CO2 with weight loss achieved through dietary management (68, 69). Although weight loss is an important long-term goal in the management of OHS, it is often difficult to achieve and maintain by medical management, and although sleep-disordered breathing is often improved it is rarely cured.
Bariatric surgery is the most effective approach to achieving more substantial degrees of weight loss and maintaining this loss over longer periods (70). Although a number of studies have shown significant improvements in lung volumes, especially expiratory reserve volume (71, 72), and gas exchange (73) can be achieved with surgical weight loss, few of these studies have specifically looked at outcomes in patients with OHS (71, 74). Most commonly, bariatric surgery is performed in morbidly obese women, in whom the prevalence of OHS is lower than in men (45). In a study looking at the prevalence of sleep-disordered breathing in consecutive premenopausal women presenting for bariatric surgery, 8% of the study group were found to have OHS (75). However, details regarding postoperative complications and longer-term outcomes were not provided. Although significant improvements in sleep-disordered breathing occur after surgical weight loss, a recent metaanalysis found that the apnea-hypopnea index remained high in many individuals (76). The presence of persisting sleep-disordered breathing is often not recognized, and patients may be reluctant to undergo a postsurgical sleep breathing evaluation if they perceive their sleep symptoms have resolved (77). Consequently, this could lead to a substantial number of patients ceasing PAP therapy prematurely after surgery (78).
The surgical approach to weight loss is being increasingly used in super obese (BMI > 50 kg/m2) and super-super obese individuals (> 60 kg/m2) (79, 80). Although significant and sustained weight loss in these groups was reported, only one in three patients achieved a reduction in BMI below 40 kg/m2 (79). The need for and compliance with PAP therapy in these super obese patients postsurgery has not been addressed, nor have longer-term cardiovascular outcomes been adequately monitored. Given general data on the relatively low level of complications of bariatric surgery in experienced centers (80), consideration should be given to more detailed research involving this approach in the long-term management of OHS.
Although we are developing a better understanding of the complex interactions involved in the development of OHS, there is still the need for earlier diagnosis and more effective management and follow-up strategies. This will require better understanding of the epidemiology of OHS and particularly which patients with obesity and sleep-disordered breathing develop this condition over time. The emergence of an increasing number of super obese individuals will pose management challenges in the near future. Although improved breathing during sleep and wakefulness can generally be achieved with PAP therapy, the lack of large-scale, well-designed studies evaluating long-term outcomes with various therapies has limited the development of evidence-based treatment recommendations. Endpoints of therapy need to be defined by appropriate clinical trials. This will require a coordinated multicenter approach. Given the significant morbidity and mortality associated with untreated or poorly managed disease, more information is needed regarding barriers to using therapy and outcomes for patients in whom response to therapy is incomplete. Finally, the extent to which surgical and new nonsurgical weight-loss approaches impact on longer-term outcomes in OHS compared with PAP therapy warrants further evaluation.
| 1. | Sturm R. Increases in morbid obesity in the USA: 2000–2005. Public Health 2007;121:492–496. |
| 2. | Berger KI, Ayappa I, Chatr-Amontri B, Marfatia A, Sorkin IB, Rapoport DM, Goldring RM. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest 2001;120:1231–1238. |
| 3. | Ward S, Chatwin M, Heather S, Simonds AK. Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005;60:1019–1024. |
| 4. | Kessler R, Chaouat A, Schinkewitch P, Faller M, Casel S, Krieger J, Weitzenblum E. The obesity-hypoventilation syndrome revisited: A prospective study of 34 consecutive cases. Chest 2001;120:369–376. |
| 5. | Laaban J-P, Chailleux E; Observatory Group of ANTADIR. Daytime hypercapnia in adult patients with obstructive sleep apnea syndrome in france, before initiating nocturnal nasal continuous positive airway pressure therapy. Chest 2005;127:710–715. |
| 6. | Mokhlesi B, Tulaimat A, Faibussowitsch I, Wang Y, Evans A. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007;11:117–124. |
| 7. | Nowbar S, Burkart KM, Gonzales R, Fedorowicz A, Gozansky WS, Gaudio JC, Taylor MRG, Zwillich CW. Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med 2004;116:1–7. |
| 8. | Kaw R, Hernandez AV, Walker E, Aboussouan L, Mokhlesi B. Determinants of hypercapnia in obese patients with obstructive sleep apnea: a systematic review and metaanalysis of cohort studies. Chest 2009;136:787–796. |
| 9. | Mokhlesi B, Saager L, Kaw RQ. Should we routinely screen for hypercapnia in sleep apnea patients before elective noncardiac surgery? Cleve Clin J Med 2010;77:60–61. |
| 10. | Piper AJ, Grunstein RR. Big breathing: the complex interaction of obesity, hypoventilation, weight loss, and respiratory function. J Appl Physiol 2010;108:199–205. |
| 11. | Resta O, Foschino-Barbaro MP, Bonfitto P, Talamo S, Legari G, De Pergola G, Minenna A, Giorgino R. Prevalence and mechanisms of diurnal hypercapnia in a sample of morbidly obese subjects with obstructive sleep apnea. Respir Med 2000;94:240–246. |
| 12. | Behazin N, Jones SB, Cohen RI, Loring SH. Respiratory restriction and elevated pleural and esophageal pressures in morbid obesity. J Appl Physiol 2010;108:212–218. |
| 13. | Pelosi P, Croci M, Ravagnan I, Vicardi P, Gattinoni L. Total respiratory system, lung, and chest wall mechanics in sedated-paralyzed postoperative morbidly obese patients. Chest 1996;109:144–151. |
| 14. | Zerah F, Harf A, Perlemuter L, Lorino H, Lorino AM, Atlan G. Effects of obesity on respiratory resistance. Chest 1993;103:1470–1476. |
| 15. | Pankow W, Podszus T, Gutheil T, Penzel T, Peter J, Von Wichert P. Expiratory flow limitation and intrinsic positive end-expiratory pressure in obesity. J Appl Physiol 1998;85:1236–1243. |
| 16. | Steier J, Jolley CJ, Seymour J, Roughton M, Polkey MI, Moxham J. Neural respiratory drive in obesity. Thorax 2009;64:719–725. |
| 17. | Lee MY, Lin CC, Shen SY, Chiu CH, Liaw SF. Work of breathing in eucapnic and hypercapnic sleep apnea syndrome. Respiration 2009;77:146–153. |
| 18. | Borel J-C, Roux-Lombard P, Tamisier R, Arnaud C, Monneret D, Arnol N, Baguet J-P, Levy P, Pepin J-L. Endothelial dysfunction and specific inflammation in obesity hypoventilation syndrome. PLoS ONE 2009;4:e6733. |
| 19. | Sharp JT, Druz WS, Kondragunta VR. Diaphragmatic responses to body position changes in obese patients with obstructive sleep apnea. Am Rev Respir Dis 1986;133:32–37. |
| 20. | Lazarus R, Sparrow D, Weiss ST. Effects of obesity and fat distribution on ventilatory function: the normative aging study. Chest 1997;111:891–898. |
| 21. | Zavorsky GS, Wilson B. Sex, girth, waists and hips (what matters for gas exchange in extreme obesity?). Respir Physiol Neurobiol 2010;170:120–122. |
| 22. | Piper AJ, Wang D, Yee BJ, Barnes DJ, Grunstein RR. Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation. Thorax 2008;63:395–401. |
| 23. | De Miguel Diez J, De Lucas Ramos P, Perez Parra JJ, Buendia Garcia MJ, Cubillo Marcos JM, Gonzalez-Moro JM. Analysis of withdrawal from noninvasive mechanical ventilation in patients with obesity-hypoventilation syndrome: medium term results. Arch Bronconeumol 2003;39:292–297. |
| 24. | Ayappa I, Berger KI, Norman RG, Oppenheimer BW, Rapoport DM, Goldring RM. Hypercapnia and ventilatory periodicity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166:1112–1115. |
| 25. | Berger KI, Goldring RM, Rapoport DM. Obesity hypoventilation syndrome. Semin Respir Crit Care Med 2009;30:253–261. |
| 26. | Lee S-D, Nakano H, Farkas GA. Adenosinergic modulation of ventilation in obese Zucker rats. Obes Res 2005;13:545–555. |
| 27. | Yang AL, Lo MJ, Ting H, Chen JS, Huang CY, Lee SD. GABA(a) and GABA(b) receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats. J Appl Physiol 2007;102:350–357. |
| 28. | Hlavac MC, Catcheside PG, McDonald R, Eckert DJ, Windler S, McEvoy RD. Hypoxia impairs the arousal response to external resistive loading and airway occlusion during sleep. Sleep 2006;29:624–631. |
| 29. | Burki NK, Baker RW. Ventilatory regulation in eucapnic morbid obesity. Am Rev Respir Dis 1984;129:538–543. |
| 30. | Sampson MG, Grassino K. Neuromechanical properties in obese patients during carbon dioxide rebreathing. Am J Med 1983;75:81–90. |
| 31. | Lopata M, Onal E. Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation. Am Rev Respir Dis 1982;126:640–645. |
| 32. | Chouri-Pontarollo N, Borel JC, Tamisier R, Wuyam B, Levy P, Pepin JL. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: Impact of noninvasive ventilation. Chest 2007;131:148–155. |
| 33. | Monneret D, Borel JC, Pepin JL, Tamisier R, Arnol N, Levy P, Faure P. Pleiotropic role of IGF-1 in obesity hypoventilation syndrome. Growth Horm IGF Res 2010;20:127–133. |
| 34. | Zwillich CW, Sutton FD, Pierson DJ, Greagh EM, Weil JV. Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med 1975;59:343–348. |
| 35. | Javaheri S, Colangelo G, Corser B, Zahedpour MR. Familial respiratory chemosensitivity does not predict hypercapnia of patients with sleep apnea-hypopnea syndrome. Am Rev Respir Dis 1992;145:837–840. |
| 36. | Jokic R, Zintel T, Sridhar G, Gallagher CG, Fitzpatrick MF. Ventilatory responses to hypercapnia and hypoxia in relatives of patients with the obesity hypoventilation syndrome. Thorax 2000;55:940–945. |
| 37. | Tankersley CG, O'Donnell C, Daood MJ, Watchko JF, Mitzner W, Schwartz A, Smith P. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol 1998;85:2261–2269. |
| 38. | Phipps PR, Starritt E, Caterson I, Grunstein RR. Association of serum leptin with hypoventilation in human obesity. Thorax 2002;57:75–76. |
| 39. | Shimura R, Tatsumi K, Nakamura A, Kasahara Y, Tanabe N, Takiguchi Y, Kuriyama T. Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest 2005;127:543–549. |
| 40. | Campo A, Fruhbeck G, Zulueta JJ, Iriarte J, Seijo LM, Alcaide AB, Galdiz JB, Salvador J. Hyperleptinemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J 2007;30:223–231. |
| 41. | Trevaskis JL, Parkes DG, Roth JD. Insights into amylin-leptin synergy. Trends Endocrinol Metab 2010;21:473–479. |
| 42. | Grunstein RR, Ho KY, Berthon-Jones M, Stewart D, Sullivan CE. Central sleep apnea is associated with increased ventilatory response to carbon dioxide and hypersecretion of growth hormone in patients with acromegaly. Am J Respir Crit Care Med 1994;150:496–502. |
| 43. | Banerjee D, Yee BJ, Piper AJ, Zwillich CW, Grunstein RR. Obesity hypoventilation syndrome: hypoxemia during continuous positive airway pressure. Chest 2007;131:1678–1684. |
| 44. | Perez de Llano LA, Golpe R, Ortiz Piquer M, Veres Racamonde A, Vazquez Caruncho M, Caballero Muinelos O, Alvarez Carro C. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005;128:587–594. |
| 45. | Mokhlesi B, Kryger MH, Grunstein RR. Assessment and management of patients with obesity hypoventilation syndrome. Proc Am Thorac Soc 2008;5:218–225. |
| 46. | Quint JK, Ward L, Davison AG. Previously undiagnosed obesity hypoventilation syndrome. Thorax 2007;62:462–463. |
| 47. | Berg G, Delaive K, Manfreda J, Walld R, Kryger MH. The use of health-care resources in obesity-hypoventilation syndrome. Chest 2001;120:377–383. |
| 48. | Priou P, Hamel J-F, Person C, Meslier N, Racineux J-L, Urban T, Gagnadoux F. Long-term outcome of noninvasive positive pressure ventilation for obesity hypoventilation syndrome. Chest 2010;138:84–90. |
| 49. | Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384. |
| 50. | Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034–2041. |
| 51. | Budweiser S, Riedl SG, Jorres RA, Heinemann F, Pfeifer M. Mortality and prognostic factors in patients with obesity-hypoventilation syndrome undergoing noninvasive ventilation. J Intern Med 2007;261:375–383. |
| 52. | Hida W, Okabe S, Tatsumi K, Kimura H, Akasiba T, Chin K, Ohi M, Nakayama H, Satoh M, Kuriyama T. Nasal continuous positive airway pressure improves quality of life in obesity hypoventilation syndrome. Sleep Breath 2003;7:3–12. |
| 53. | Windisch W. Impact of home mechanical ventilation on health-related quality of life. Eur Respir J 2008;32:1328–1336. |
| 54. | Budweiser S, Hitzl A, Jorres R, Schmidbauer K, Heinemann F, Pfeifer M. Health-related quality of life and long-term prognosis in chronic hypercapnic respiratory failure: a prospective survival analysis. Respir Res 2007;8:92. |
| 55. | Cabrera Lacalzada C, Diaz-Lobato S. Grading obesity hypoventilation syndrome severity. Eur Respir J 2008;32:817–818. |
| 56. | Piper A. Obesity hypoventilation syndrome: therapeutic implications for treatment. Expert Rev Respir Med 2010;4:57–70. |
| 57. | Mechanick JI, Kushner RF, Sugerman HJ, Gonzalez-Campoy JM, Collazo-Clavell ML, Spitz AF, Apovian CM, Livingston EH, Brolin R, Sarwer DB, et al. American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Obesity (Silver Spring) 2009;17:S1–S70. |
| 58. | Morgenthaler TI, Aurora N, Brown T, Zak R, Alessi C, Boehlecke B, Chesson AL, Friedman L, Kapur V, Maganti R, et al. Practice parameters for the use of autotitrating continuous positive airway pressure devices for titrating pressures and treating adult patients with obstructive sleep apnea syndrome: an update for 2007. Sleep 2008;31:141–147. |
| 59. | Storre JH, Seuthe B, Fiechter R, Milioglou S, Dreher M, Sorichter S, Windisch W. Average volume-assured pressure support in obesity hypoventilation: a randomized crossover trial. Chest 2006;130:815–821. |
| 60. | Maniscalco M, Zedda A, Faraone S, Carratu P, Sofia M. Evaluation of a transcutaneous carbon dioxide monitor in severe obesity. Intensive Care Med 2008;34:1340–1344. |
| 61. | Mokhlesi B, Tulaimat A, Evans AT, Wang Y, Itani AA, Hassaballa HA, Herdegen JJ, Stepanski EJ. Impact of adherence with positive airway pressure therapy on hypercapnia in obstructive sleep apnea. J Clin Sleep Med 2006;2:57–62. |
| 62. | Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest 2007;132:1322–1336. |
| 63. | Perez de Llano LA, Golpe R, Ortiz Piquer M, Veres Racamonde A, Vazquez Caruncho M, Lopez MJ, Farinas MC. Clinical heterogeneity among patients with obesity hypoventilation syndrome: therapeutic implications. Respiration 2008;75:34–39. |
| 64. | Janssens JP, Metzger M, Sforza E. Impact of volume targeting on efficacy of bi-level non-invasive ventilation and sleep in obesity-hypoventilation. Respir Med 2009;103:165–172. |
| 65. | Kim SH, Eisele DW, Smith PL, Schneider H, Schwartz AR. Evaluation of patients with sleep apnea after tracheotomy. Arch Otolaryngol Head Neck Surg 1998;124:996–1000. |
| 66. | Rapoport DM, Garay SM, Epstein H, Goldring RM. Hypercapnia in the obstructive sleep apnea syndrome. A reevaluation of the “Pickwickian syndrome”. Chest 1986;89:627–635. |
| 67. | El Solh AA, Jaafar W. A comparative study of the complications of surgical tracheostomy in morbidly obese critically ill patients. Crit Care 2007;11:R3. |
| 68. | Burwell CS, Robin ED, Whaley RD, Bickelmann AG. Extreme obesity associated with alveolar hypoventilation; a pickwickian syndrome. Am J Med 1956;21:811–818. |
| 69. | Rochester DF, Enson Y. Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Mechanical and circulatory factors. Am J Med 1974;57:402–420. |
| 70. | Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741–752. |
| 71. | Sugerman HJ, Fairman RP, Baron PL, Kwentus JA. Gastric surgery for respiratory insufficiency of obesity. Chest 1986;90:81–86. |
| 72. | Thomas PS, Cowen ER, Hulands G, Milledge JS. Respiratory function in the morbidly obese before and after weight loss. Thorax 1989;44:382–386. |
| 73. | Zavorsky GS, Hoffman SL. Pulmonary gas exchange in the morbidly obese. Obes Rev 2008;9:326–339. |
| 74. | Boone KA, Cullen JJ, Mason EE, Scott DH, Doherty C, Maher JW. Impact of vertical banded gastroplasty on respiratory insufficiency of severe obesity. Obes Surg 1996;6:454–458. |
| 75. | Lecube A, Sampol G, Lloberes P, Romero O, Mesa J, Morell F, Simo R. Asymptomatic sleep-disordered breathing in premenopausal women awaiting bariatric surgery. Obes Surg 2010;20:454–461. |
| 76. | Greenburg DL, Lettieri CJ, Eliasson AH. Effects of surgical weight loss on measures of obstructive sleep apnea: a meta-analysis. Am J Med 2009;122:535–542. |
| 77. | Dixon JB, Schachter LM, O'Brien PE. Polysomnography before and after weight loss in obese patients with severe sleep apnea. Int J Obes 2005;29:1048–1054. |
| 78. | Lettieri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med 2008;4:333–338. |
| 79. | Helling TS. Operative experience and follow-up in a cohort of patients with a BMI ≥ 70 kg/m2. Obes Surg 2005;15:482–485. |
| 80. | Torchia F, Mancuso V, Civitelli S, Di Maro A, Cariello P, Rosano PT, Sionne GC, Lorenzo M, Cascardo AJ. Lapband system in super-superobese patients (>60 kg/m2): 4-year results. Obes Surg 2009;19:1211–1215. |
| 81. | Piper AJ. Obesity hypoventilation syndrome: the big and the breathless. Sleep Med Rev (In press) |
