Abstract
Obesity hypoventilation syndrome (OHS) is characterized by obesity, daytime hypercapnia, and sleep-disordered breathing in the absence of significant lung or respiratory muscle disease. Compared with eucapnic morbidly obese patients and eucapnic patients with sleep-disordered breathing, patients with OHS have increased health care expenses and are at higher risk of developing serious cardiovascular disease leading to early mortality. Despite the significant morbidity and mortality associated with this syndrome, diagnosis and institution of effective treatment occur late in the course of the syndrome. Given that the prevalence of extreme obesity has increased considerably, it is likely that clinicians will encounter patients with OHS in their clinical practice. Therefore maintaining a high index of suspicion can lead to early recognition and treatment reducing the high burden of morbidity and mortality and related health care expenditure associated with undiagnosed and untreated OHS. In this review we define the clinical characteristics of the syndrome and review the pathophysiology, morbidity, and mortality associated with it. Last, we discuss currently available treatment modalities.
In the United States, the prevalence of extreme obesity (body mass index [BMI] ≥ 40 kg/m2) is increasing rapidly. From 1986 to 2000, the prevalence of BMI of at least 40 kg/m2 quadrupled and that of BMI of at least 50 kg/m2 increased by fivefold (1, 2). Unfortunately, the obesity epidemic is a global phenomenon affecting not just adults, but also children and adolescents (3–6). With such a global epidemic of extreme obesity the prevalence of obesity hypoventilation syndrome (OHS) is likely to increase and therefore clinicians need to maintain a high index of suspicion, particularly given that early recognition and treatment reduce the high burden of morbidity and mortality associated with this syndrome.
Auchincloss and coworkers, in 1955, described in detail a patient with OHS (7) and the following year, Burwell and colleagues compared patients with OHS with an obese, somnolent Charles Dickens character and popularized the description “Pickwickian syndrome” (8). The central features of OHS, as currently accepted, include obesity (BMI ≥ 30 kg/m2), chronic alveolar hypoventilation leading to daytime hypercapnia and hypoxia (PaCO2 ≥ 45 mm Hg and PaO2 < 70 mm Hg), and sleep-disordered breathing (9–11). Essential to the diagnosis is exclusion of other causes of alveolar hypoventilation such as severe obstructive or restrictive pulmonary disease, significant kyphoscoliosis, severe hypothyroidism, neuromuscular diseases, or other central hypoventilation syndromes. Although OHS can exist autonomously, it is frequently associated with obstructive sleep apnea (OSA), which is characterized by recurrent upper airway obstruction resulting in apneas, hypopneas, oxygen desaturation, and arousals from sleep. In approximately 90% of patients with OHS the sleep-disordered breathing consists of OSA. The remaining 10% of patients with OHS have an apnea–hypopnea index less than 5 (10, 12, 13). The sleep-disordered breathing in this subset of patients has been labeled as sleep hypoventilation and is defined as an increase in PaCO2 during sleep by 10 mm Hg above wakefulness or significant oxygen desaturation that is not explained by obstructive apneas or hypopneas.
The precise prevalence of OHS in the general population remains uncertain because no general population-based studies have been performed to examine this issue. However, the prevalence of OHS among patients with OSA has been estimated as between 10 and 20% (10, 12, 14–18) and is higher in the subgroup of patients with extreme obesity (Table 1 and Figure 1) (10, 15, 19).
Figure 1. Prevalence of obesity hypoventilation syndrome (OHS) in patients with obstructive sleep apnea (OSA) by categories of body mass index (BMI) in the United States (10), France (15), and Italy. The data from Italy were provided by O. Resta (University of Bari, Bari, Italy). In the study from the United States the mean BMI was 43 kg/m2 and 60% of the subjects had a BMI above 40 kg/m2. In contrast, the mean BMI in the French study was 34 kg/m2 and 15% of the subjects had a BMI above 40 kg/m2. Consequently, OHS may be more prevalent in the United States compared with other nations because of its more exuberant obesity epidemic. Reprinted by permission from Reference 11.
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Authors | n | Design | Country | Age (yr) | BMI | AHI | OHS (%) |
|---|---|---|---|---|---|---|---|
| Verin and colleagues (17) | 218 | Retrospective | France | 55 | 34 | 51 | 10 |
| Laaban and Chailleux (15) | 1,141 | Retrospective | France | 56 | 34 | 55 | 11 |
| Kessler and colleagues (12) | 254 | Prospective | France | 54 | 33 | 76 | 13 |
| Resta and colleagues (16) | 219 | Prospective | Italy | 51 | 40 | 42 | 17 |
| Golpe and colleagues (18) | 175 | Retrospective | Spain | NA | 32 | 42 | 14 |
| Akashiba and colleagues (14) | 611 | Retrospective | Japan | 48 | 29 | 52 | 9 |
| Mokhlesi and colleagues. (10) | 359 | Prospective | USA | 48 | 43 | 62 | 20 |
Although most patients with OHS have had prior hospitalizations, in the majority of these patients the formal diagnosis of OHS is established late, in the fifth or sixth decade of life, after consultation with a pulmonary and critical care specialist (12, 20, 21). The vast majority of patients have the classic symptoms of OSA including loud snoring, nocturnal choking episodes with witnessed apneas, excessive daytime sleepiness, and morning headaches. In contrast to eucapnic OSA, patients with stable OHS frequently complain of dyspnea and may have signs of cor pulmonale. Physical examination findings can include a plethoric obese patient with an enlarged neck circumference, crowded oropharynx, a prominent P2 on cardiac auscultation (this is often difficult to hear because of obesity), and lower extremity edema. Table 2 summarizes the clinical features of 757 patients with OHS reported in the literature (10, 12–19, 21–27).
Variable | Mean (range) |
|---|---|
| Age, yr | 52 (42–61) |
| Men, % | 60 (49–90) |
| Body mass index, kg/m2 | 44 (35–56) |
| Neck circumference, cm | 46.5 (45–47) |
| pH | 7.38 (7.34–7.40) |
| PaCO2, mm Hg | 53 (47–61) |
| PaO2, mm Hg | 56 (46–74) |
| Serum bicarbonate, mEq/L | 32 (31–33) |
| Hemoglobin, g/dl | 15 |
| Apnea–hypopnea index | 66 (20–100) |
| Oxygen nadir during sleep, % | 65 (59–76) |
| Percent time SaO2 less than 90%, % | 50 (46–56) |
| FVC, %pred | 68 (57–102) |
| FEV1, %pred | 64 (53–92) |
| FEV1/FVC | 77 (74–88) |
| Medical Research Council dyspnea class 3 and 4, % | 69 |
| Epworth Sleepiness Scale, score | 14 (12–16) |
Several laboratory findings are supportive of OHS, yet the definitive test for alveolar hypoventilation is an arterial blood gas performed on room air. Elevated serum bicarbonate level due to metabolic compensation of respiratory acidosis is common in patients with OHS and points toward the chronic nature of hypercapnia (13, 21, 28), and could be used as a sensitive test to screen for hypercapnia (10). In addition, hypoxemia detected on room air pulse oximetry during wakefulness in patients with sleep-disordered breathing should prompt clinicians to exclude hypercapnia (10, 29). If hypercapnia is present, pulmonary function testing and chest imaging should be performed to exclude other causes of hypercapnia. Pulmonary function tests can be normal but typically reveal a mild to moderate restrictive defect due to body habitus without significant reduction in FEV1/FVC accompanied by a significant reduction in the expiratory reserve volume. Patients with OHS may also have mild reductions in maximal expiratory and inspiratory pressures related to the combination of abnormal respiratory mechanics and weak respiratory muscles (30). Other laboratory testing should include a complete blood count to rule out secondary erythrocytosis and severe hypothyroidism.
The mechanism by which morbid obesity leads to hypoventilation is complex and not fully understood. Several mechanisms have been proposed in the pathogenesis of OHS, including abnormal respiratory system mechanics due to obesity, impaired central responses to hypercapnia and hypoxia, sleep-disordered breathing, and neurohormonal abnormalities such as leptin resistance (Figure 2).
Obesity imposes a significant mechanical load leading to a reduction in total respiratory system compliance (16, 19, 23, 31, 32), increased lung resistance (33, 34), and a relative state of respiratory muscle weakness leading to increased work of breathing (30, 34–36). However, it does not appear that obesity is the only determinant of hypoventilation as less than one-third of morbidly obese patients develop chronic hypercapnia (10, 15). Other determinants of hypoventilation include a blunted central responsiveness to hypercapnia and hypoxia (25, 28, 35, 37–39), a state of leptin resistance (a satiety protein that increases ventilation) (40–43), and sleep-disordered breathing. The role of sleep-disordered breathing in the pathogenesis of hypoventilation has been well established by the resolution of hypercapnia in the majority of patients with OHS with either positive airway pressure therapy or tracheostomy without any concomitant change in body mass (13, 22, 25, 26, 28, 44–46), CO2 production, or the volume of dead space (28).
A model that combines sleep-disordered breathing, central respiratory drive, and renal buffering has been proposed to explain the pathophysiology of OHS (47–49). In patients with OSA, the minute ventilation during sleep does not decrease, due to the large increase in the minute ventilation between the obstructive respiratory events. Obstructive respiratory events can, however, lead to acute hypercapnia if the duration of the interevent hyperventilation is inadequate to eliminate the accumulated CO2 (50). This acute hypercapnia causes a small increase in serum bicarbonate level that is not corrected before the next sleep period if the time constant of bicarbonate excretion is longer than that of CO2 (48). The elevated bicarbonate level blunts the ventilatory response to CO2 from its initial value by reducing the change in hydrogen ions for a given change in CO2 and would ultimately result in a higher awake CO2 level (47, 51–53).
Because the defining pathogenic characteristics in OHS are obesity and respiratory failure, not surprisingly the morbidity documented clinically will be most often related to these two factors. Berg and colleagues showed that patients with OHS use much more health care than do obese patients without hypoventilation or general population control subjects in the 5 years before OHS is actually confirmed (24). By comparing health care use in cases versus obese and general population control subjects, this group was able to tease apart the comorbidities related to the obesity per se and those related to hypoventilation.
Compared with obese control subjects, patients with OHS were statistically much more likely to have been diagnosed with congestive heart failure (odds ratio [OR], 9; 95% confidence interval [95% CI], 2.3–35), angina pectoris (OR, 9; 95% CI, 1.4–57.1), and cor pulmonale (OR, 9; 95% CI, 1.4–57.1) (24). Patients with OHS were more likely to be hospitalized and, compared with patients with a similar degree of obesity but without hypoventilation, had higher rates of admission to the intensive care unit and need for invasive mechanical ventilation (21, 24).
Obesity is associated with many medical problems and is a component of the metabolic syndrome. Consequently, patients with OHS are at increased risk of morbidities that span several organ systems in addition to those related to hypoventilation. Specifically, they are much more likely to be diagnosed with arterial hypertension (OR, 3.8; 95% CI, 1.5–9.8), diabetes mellitus (OR, 17.2; 95% CI, 7.3–40.7), hypothyroidism (OR, 6.5; 95% CI, 2.4–17.5), and osteoarthritis (OR, 3.3; 95% CI, 1.1–10.3) (24). Also probably related to obesity, there is an increased risk of hepatic dysfunction and hyperlipidemia (14). Others have reported that patients with OHS have a higher rate of pulmonary hypertension compared with eucapnic patients with OSA (12, 54). Up to one-quarter of patients with OHS also carry a diagnosis of asthma (13, 26). It is not surprising, given the large number of comorbidities, that patients with OHS have impaired quality of life compared with eucapnic patients with OSA matched for age, BMI, and lung function (55).
Although older series had reported a high mortality rate among hospitalized patients with OHS (56, 57), two prospective studies reported no in-hospital deaths among a total of 64 consecutive hospitalized patients with OHS (21, 58). Of course, respiratory failure, if untreated, places these patients at markedly increased risk of death. A retrospective study reported that 7 of 15 patients with OHS who refused long-term noninvasive positive airway pressure (NPPV) therapy died during an average follow-up period of 50 months (13). Similarly, a prospective study monitored 47 untreated patients with OHS for 18 months after hospital discharge. The mortality of patients with OHS was 23 versus 9% in patients with a similar degree of obesity but without hypoventilation (hazards ratio of 4.0 after adjusting for age, sex, BMI, and renal function) and most deaths occurred in the first 3 months after hospital discharge (21). In contrast, one retrospective study of 126 patients with OHS who were adherent with NPPV therapy reported an 18-month mortality of 3% (Figure 3), and the 2- and 5-year mortality rates were 8 and 30%, respectively (27). Moreover, current evidence also suggests that adherence with positive airway pressure therapy reduces health care expenses and hospital readmission rates among patients with OHS (13, 24, 45).
Figure 3. Survival curves for patients with untreated obesity hypoventilation syndrome (OHS) (n = 47; mean age, 55 ± 14 yr; mean body mass index [BMI], 45 ± 9 kg/m2; mean PaCO2, 52 ± 7 mm Hg) and eucapnic, morbidly obese patients (n = 103; mean age, 53 ± 13 yr; mean BMI, 42 ± 8 kg/m2) as reported by Nowbar and colleagues (21) compared with patients with OHS treated with noninvasive positive airway pressure (NPPV) therapy (n = 126; mean age, 55.6 ± 10.6 yr; mean BMI, 44.6 ± 7.8 kg/m2; mean baseline PaCO2, 55.5 ± 7.7 mm Hg; mean adherence with NPPV, 6.5 ± 2.3 h/d). Data for patients with OHS treated with NPPV were provided by S. Budweiser and colleagues (University of Regensburg, Regensburg, Germany) (27). Modified by permission from Reference 21.
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Collectively, the foregoing evidence would suggest that identifying patients with OHS in a timely manner is important and treatment should be initiated without delay to avoid adverse outcomes such as readmission to the hospital, acute-on-chronic respiratory failure requiring intensive care monitoring, and death.
There are no established guidelines on treatment of OHS. In effect, treatment modalities are each based on different perspectives concerning the underlying pathophysiology of the condition. First, upper airway obstruction is an important factor in the pathogenesis of OHS and there is evidence that strategies for reversing upper airway obstruction, such as tracheostomy and nasal continuous positive airway pressure (CPAP), are effective. Second, failure of normal mechanisms that prevent hypoventilation during sleep are implicated in OHS and therefore noninvasive or even invasive ventilation to support breathing and reverse hypoventilation has been advocated. Alternatively, pharmacologic methods to stimulate breathing have been used. Finally, by definition, OHS does not occur in the absence of obesity. Therefore, methods that result in major weight reduction will effectively reverse OHS.
Kuhlo and colleagues first described the use of tracheostomy to reverse Pickwickian syndrome in 1969 (59). It was observed that this therapy could not only reverse sleep-related respiratory failure but also awake hypoventilation in most cases (28, 60, 61). There was also a report of a mechanical device (a supportive collar designed to hold the mandible forward) reversing upper airway obstruction during sleep and improving awake respiratory failure (62). After the advent of nasal CPAP, this therapy was used in patients with OHS, resulting in remission of awake respiratory failure (63, 64). Subsequent reports have supported the initial observation of the efficacy of nasal CPAP alone as a treatment of OHS (26, 55, 65–67). Patients who were successfully treated with CPAP typically required pressures of 12–14 cm H2O (13, 26, 65). However, there were also early reports of partial success or failure of nasal CPAP to reverse some cases of OHS (68) and confirmed by subsequent studies (15, 26, 65, 69, 70).
Ventilatory support via tracheostomy for obesity-related respiratory failure has been used since the 1960s. Although effective, this was obviously not an ideal technique given the difficulties of maintaining a tracheostomy, especially in patients with markedly excessive fat in the neck region. NPPV using a face or, later, nasal mask was regularly used in OHS from the late 1980s, based on effective use of this approach in patients with other forms of chest wall disease (71). Studies using bilevel positive airway pressure (PAP)—the most common mode of NPPV—or volume-cycled ventilation showed efficacy in reversing diurnal respiratory failure in patients who had failed nasal CPAP for OHS (45, 72, 73). Subsequent research has confirmed the efficacy of NPPV in OHS (13, 27, 74).
Approximately half of patients with OHS require supplemental nocturnal oxygen in addition to some form of PAP therapy (13, 26, 45, 75). The need for nocturnal and daytime oxygen therapy decreases significantly in patients adherent with PAP therapy (13, 26, 45). Supplemental oxygen without PAP therapy, however, is inadequate and does not improve hypoventilation (76).
Given the potential role of impaired respiratory control in the pathogenesis of OHS, using pharmacologic agents to stimulate breathing would be an attractive option. However, there are few data on this approach. Reports of initial positive results with either progesterone (77), almitrine (78), or acetazolamide (28) have never resulted in ongoing randomized controlled trials. Furthermore, medroxyprogesterone can increase the risk of venous thromboembolism (79, 80).
Research using a putative animal model of OHS, the leptin-deficient ob/ob mouse, has demonstrated improvement in awake respiratory failure with leptin replacement (81). This has never been verified in humans, where leptin resistance, rather than leptin deficiency, is present (41).
Starting with the original report by Burwell and colleagues (8), a number of subsequent studies have identified that weight loss results in improvement in sleep-disordered breathing, reduction in awake respiratory failure, and improvement in lung function in patients with OHS. Rapid weight reduction can be achieved by a range of surgical methods, although most data concerning OHS are available from surgical procedures such as gastric bypass or gastric banding (54, 82, 83). The significant weight loss associated with bariatric surgery can improve ventilation during sleep, which can eventually lead to improvement in diurnal ventilation (84).
Patients with OHS are at increased risk of death related to gastric bypass surgery, in part because of the increased risk of postoperative respiratory failure and the development of pulmonary embolism (85). Appropriate management in such patients undergoing surgery should include perioperative treatment with PAP therapy until weight loss results in enough improvement of disordered breathing during sleep that withdrawal of therapy is allowed. Therefore, we believe that patients with OHS should be treated with CPAP or bilevel PAP preoperatively and immediately after extubation to avoid postoperative respiratory failure (86–88). Furthermore, there is no evidence that PAP therapy used during the immediate postoperative period leads to increased risk of anastomotic disruption or intestinal leakage (89). In the long term, weight reduction provides the most effective solution to OHS. Evidence is accumulating that in patients with OHS bariatric surgery may be the best option in treating the multitude of comorbidities that are related to extreme obesity such as hypertension, hyperlipidemia, and type 2 diabetes (90). However, weight gain and significant increase in the apnea–hypopnea index can occur between 3 and 7 years after gastric bypass surgery (91).
Clearly treatment of OHS will depend on the state of the patient at presentation. In extreme cases patients with OHS may present with decompensated respiratory failure. Although there are reports that nasal CPAP may be effective in these situations (67), clinical consensus suggests such patients should receive NPPV (13, 45, 72, 73). Figure 4 provides a general approach to the management of patients with OHS hospitalized because of acute-on-chronic hypercapnic respiratory failure (92).
Figure 4. Management of patients with OHS requiring hospitalization because of acute-on-chronic hypercapnic respiratory failure. EPAP = expiratory positive airway pressure; ICU = intensive care unit; IPAP = inspiratory positive airway pressure; RR = respiratory rate; SpO2 = oxygen saturation by pulse oximetry.
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More commonly, however, patients with OHS will present to ambulatory settings such as sleep disorders clinics or in a semielective consultation setting in hospital with stable awake respiratory failure without impaired consciousness. Most studies indicate that patients with stable OHS should undergo an initial titration with nasal CPAP and, when there is persistent moderate hypoxemia despite adequate resolution of upper airway obstruction with CPAP, bilevel PAP should then be considered (26, 65). There is no standard protocol for bilevel PAP titration in stable patients with OHS. However, the titration protocol followed in most studies consisted of increasing the expiratory PAP (EPAP) to abolish apneas, hypopneas, and any evidence of flow limitation and, if the oxygen saturation remained persistently below 90%, then inspiratory PAP (IPAP) was added to the final EPAP to improve ventilation. To achieve long-term improvement in daytime hypercapnia and hypoxia with bilevel PAP the IPAP needs to be at least 8 to 10 cm H2O above EPAP and most patients with OHS require inspiratory pressures of 16–20 cm H2O and expiratory pressures of 6–10 cm H2O (11, 13, 22, 46, 93). In the subset of patients with OHS who do not have obstructive sleep apnea EPAP can be set at 5 cm H2O and IPAP can be titrated to improve ventilation (46, 93). Whether the persistent moderate hypoxemia improves over time with CPAP remains to be elucidated (69). Some have also advocated adding low-flow oxygen to CPAP in these situations, similar to patients with overlap syndrome (OSA plus chronic obstructive pulmonary disease), but this approach has not been investigated in any detail and has not been compared to NPPV with bilevel PAP without supplemental oxygen (69). CPAP is also a less costly therapy than bilevel PAP and there is evidence that a majority of patients with OHS will have immediate improvement with CPAP alone (26, 65). There are no published large-scale randomized controlled trials that inform on best management practice in these patients (studies comparing initial treatment with CPAP or NPPV). If patients with CPAP failure due to persisting marked hypoxemia while undergoing this therapy are excluded, then preliminary data suggest that the remaining patients will have similar outcomes with CPAP at 3 months as with bilevel PAP (94). Perez de Llano and coworkers reported that up to one-third of patients with OHS who were initially treated with a few months of NPPV could be successfully switched to CPAP therapy as long as a repeat polysomnogram did not reveal significant and persistent oxygen desaturation (arbitrarily defined as oxygen saturation below 90% for at least 15% of the sleep period) despite adequate CPAP titration (13). In fact, more recently the same group of investigators reported long-term success in patients who were switched to CPAP therapy (95). Predictors of CPAP failure include greater degrees of obesity, significant restrictive chest physiology, severity of hypoxemia during polysomnography, and higher PaCO2 levels during wakefulness (65, 70, 95).
Taken together, there is compelling evidence that CPAP is effective in the majority of patients with stable OHS, particularly in the subgroup with severe OSA. Bilevel PAP should be strongly considered in patients who fail CPAP, patients with OHS who experience acute-on-chronic respiratory failure (13, 58), and patients who have OHS without OSA (46, 93). Treatment of OHS with positive airway pressure improves blood gases, morning headaches, excessive daytime sleepiness and vigilance, dyspnea, pulmonary hypertension, leg edema, and secondary erythrocytosis (13, 45, 75, 96). Improvement in symptoms and blood gases is directly related to adherence with therapy and maximal improvement in blood gases can be achieved as early as 2 to 4 weeks (26). Therefore, early follow-up is imperative and should include repeat measurement of arterial blood gases and objective assessment of adherence with positive airway pressure as patients frequently overestimate adherence (97–99). Changes in serum bicarbonate level and pulse oximetry could be used as a less invasive measure of ventilation. After a few months of treatment with bilevel PAP a subgroup of patients may no longer need nighttime or daytime supplemental oxygen therapy. In these cases simplifying the treatment regimen by discontinuing oxygen therapy can lead to significant cost savings and decrease the amount of equipment in the patient's bedroom. Although it is possible to successfully switch this subgroup of patients with OHS from bilevel PAP to CPAP therapy, it may not add to the cost savings because many patients may have completed the initial rental period on the bilevel PAP device.
In summary, the prevalence of OHS is likely to increase because of the global obesity epidemic. A high index of suspicion can lead to early recognition of the syndrome and initiation of appropriate therapy. The treatment options other than positive airway pressure have been poorly studied and further research is needed to better understand the long-term treatment outcomes of patients with OHS. In the meantime, clinicians should encourage adherence with positive airway pressure therapy to prevent the serious adverse outcomes of untreated OHS. If positive airway pressure fails to achieve the desired results, weight reduction surgery or tracheostomy with or without pharmacotherapy with respiratory stimulants should be considered.
| 1. | Freedman DS, Khan LK, Serdula MK, Galuska DA, Dietz WH. Trends and correlates of class 3 obesity in the United States from 1990 through 2000. JAMA 2002;288:1758–1761. |
| 2. | Sturm R. Increases in clinically severe obesity in the United States, 1986–2000. Arch Intern Med 2003;163:2146–2148. |
| 3. | Prentice A, Webb F. Obesity amidst poverty. Int J Epidemiol 2006;35:24–30. |
| 4. | Skidmore PM, Yarnell JW. The obesity epidemic: prospects for prevention. QJM 2004;97:817–825. |
| 5. | Spritzer DA. Obesity epidemic migrates east. CMAJ 2004;171:1159. |
| 6. | Miech RA, Kumanyika SK, Stettler N, Link BG, Phelan JC, Chang VW. Trends in the association of poverty with overweight among US adolescents, 1971–2004. JAMA 2006;295:2385–2393. |
| 7. | Auchincloss JH Jr, Cook E, Renzetti AD. Clinical and physiological aspects of a case of obesity, polycythemia and alveolar hypoventilation. J Clin Invest 1955;34:1537–1545. |
| 8. | Burwell CS, Robin ED, Whaley RD, Bickelmann AG. Extreme obesity associated with alveolar hypoventilation: a Pickwickian syndrome. Am J Med 1956;21:811–818. |
| 9. | American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22:667–689. |
| 10. | Mokhlesi B, Tulaimat A, Faibussowitsch I, Wang Y, Evans AT. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007;11:117–124. |
| 11. | Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest 2007;132:1322–1336. |
| 12. | 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. |
| 13. | 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. |
| 14. | Akashiba T, Akahoshi T, Kawahara S, Uematsu A, Katsura K, Sakurai S, Murata A, Sakakibara H, Chin K, Hida W, et al. Clinical characteristics of obesity–hypoventilation syndrome in Japan: a multi-center study. Intern Med 2006;45:1121–1125. |
| 15. | Laaban JP, Chailleux E. 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. |
| 16. | Resta O, Foschino Barbaro MP, Bonfitto P, Talamo S, Mastrosimone V, Stefano A, Giliberti T. Hypercapnia in obstructive sleep apnoea syndrome. Neth J Med 2000;56:215–222. |
| 17. | Verin E, Tardif C, Pasquis P. Prevalence of daytime hypercapnia or hypoxia in patients with OSAS and normal lung function. Respir Med 2001;95:693–696. |
| 18. | Golpe R, Jimenez A, Carpizo R. Diurnal hypercapnia in patients with obstructive sleep apnea syndrome. Chest 2002;122:1100–1101. [Author reply, p. 1101.] |
| 19. | 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 apnoea. Respir Med 2000;94:240–246. |
| 20. | Quint JK, Ward L, Davison AG. Previously undiagnosed obesity hypoventilation syndrome. Thorax 2007;62:462–463. |
| 21. | Nowbar S, Burkart KM, Gonzales R, Fedorowicz A, Gozansky WS, Gaudio JC, Taylor MR, Zwillich CW. Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med 2004;116:1–7. |
| 22. | 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. |
| 23. | Leech JA, Onal E, Baer P, Lopata M. Determinants of hypercapnia in occlusive sleep apnea syndrome. Chest 1987;92:807–813. |
| 24. | 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. |
| 25. | Han F, Chen E, Wei H, He Q, Ding D, Strohl KP. Treatment effects on carbon dioxide retention in patients with obstructive sleep apnea–hypopnea syndrome. Chest 2001;119:1814–1819. |
| 26. | Mokhlesi B, Tulaimat A, Evans AT, Wang Y, Itani A, 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. |
| 27. | 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. |
| 28. | 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. |
| 29. | Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005;118:948–956. |
| 30. | Koenig SM. Pulmonary complications of obesity. Am J Med Sci 2001;321:249–279. |
| 31. | Javaheri S, Colangelo G, Lacey W, Gartside PS. Chronic hypercapnia in obstructive sleep apnea–hypopnea syndrome. Sleep 1994;17:416–423. |
| 32. | Lopata M, Freilich RA, Onal E, Pearle J, Lourenco RV. Ventilatory control and the obesity hypoventilation syndrome. Am Rev Respir Dis 1979;119:165–168. |
| 33. | Rubinstein I, Zamel N, DuBarry L, Hoffstein V. Airflow limitation in morbidly obese, nonsmoking men. Ann Intern Med 1990;112:828–832. |
| 34. | Sharp JT, Henry JP, Sweany SK, Meadows WR, Pietras RJ. The total work of breathing in normal and obese men. J Clin Invest 1964;43:728–739. |
| 35. | Sampson MG, Grassino K. Neuromechanical properties in obese patients during carbon dioxide rebreathing. Am J Med 1983;75:81–90. |
| 36. | Kress JP, Pohlman AS, Alverdy J, Hall JB. The impact of morbid obesity on oxygen cost of breathing ( o2resp) at rest. Am J Respir Crit Care Med 1999;160:883–886. |
| 37. | Berthon-Jones M, Sullivan CE. Time course of change in ventilatory response to CO2 with long-term CPAP therapy for obstructive sleep apnea. Am Rev Respir Dis 1987;135:144–147. |
| 38. | Lopata M, Onal E. Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation. Am Rev Respir Dis 1982;126:640–645. |
| 39. | 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. |
| 40. | 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. |
| 41. | Phipps PR, Starritt E, Caterson I, Grunstein RR. Association of serum leptin with hypoventilation in human obesity. Thorax 2002;57:75–76. |
| 42. | Yee BJ, Cheung J, Phipps P, Banerjee D, Piper AJ, Grunstein RR. Treatment of obesity hypoventilation syndrome and serum leptin. Respiration 2006;73:209–212. |
| 43. | Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996;348:159–161. |
| 44. | Leech JA, Onal E, Lopata M. Nasal CPAP continues to improve sleep-disordered breathing and daytime oxygenation over long-term follow-up of occlusive sleep apnea syndrome. Chest 1992;102:1651–1655. |
| 45. | Masa JF, Celli BR, Riesco JA, Hernandez M, Sanchez De Cos J, Disdier C. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001;119:1102–1107. |
| 46. | de Lucas-Ramos P, de Miguel-Diez J, Santacruz-Siminiani A, Gonzalez-Moro JM, Buendia-Garcia MJ, Izquierdo-Alonso JL. Benefits at 1 year of nocturnal intermittent positive pressure ventilation in patients with obesity–hypoventilation syndrome. Respir Med 2004;98:961–967. |
| 47. | Norman RG, Goldring RM, Clain JM, Oppenheimer BW, Charney AN, Rapoport DM, Berger KI. Transition from acute to chronic hypercapnia in patients with periodic breathing: predictions from a computer model. J Appl Physiol 2006;100:1733–1741. |
| 48. | Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. CO2 homeostasis during periodic breathing in obstructive sleep apnea. J Appl Physiol 2000;88:257–264. |
| 49. | Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. Postevent ventilation as a function of CO2 load during respiratory events in obstructive sleep apnea. J Appl Physiol 2002;93:917–924. |
| 50. | 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. |
| 51. | Goldring RM, Heinemann HO, Turino GM. Regulation of alveolar ventilation in respiratory failure. Am J Med Sci 1975;269:160–170. |
| 52. | Goldring RM, Turino GM, Heinemann HO. Respiratory–renal adjustments in chronic hypercapnia in man: extracellular bicarbonate concentration and the regulation of ventilation. Am J Med 1971;51:772–784. |
| 53. | Heinemann HO, Goldring RM. Bicarbonate and the regulation of ventilation. Am J Med 1974;57:361–370. |
| 54. | Sugerman HJ, Fairman RP, Baron PL, Kwentus JA. Gastric surgery for respiratory insufficiency of obesity. Chest 1986;90:81–86. |
| 55. | 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. |
| 56. | MacGregor MI, Block AJ, Ball WC Jr. Topics in clinical medicine: serious complications and sudden death in the Pickwickian syndrome. Johns Hopkins Med J 1970;126:279–295. |
| 57. | Miller A, Granada M. In-hospital mortality in the Pickwickian syndrome. Am J Med 1974;56:144–150. |
| 58. | Ortega Gonzalez A, Peces-Barba Romero G, Fernandez Ormaechea I, Chumbi Flores R, Cubero de Frutos N, Gonzalez Mangado N. Evolution of patients with chronic obstructive pulmonary disease, obesity hypoventilation syndrome or congestive heart failure in a respiratory monitoring unit. Arch Bronconeumol 2006;42:423–429. |
| 59. | Kuhlo W, Doll E, Franck MC. Successful management of Pickwickian syndrome using long-term tracheostomy. Dtsch Med Wochenschr 1969;94:1286–1290. |
| 60. | Aubert-Tulkens G, Willems B, Veriter C, Coche E, Stanescu DC. Increase in ventilatory response to CO2 following tracheostomy in obstructive sleep apnea. Bull Eur Physiopathol Respir 1980;16:587–593. |
| 61. | 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. |
| 62. | Hensley MJ, Read DJ. Intemittent obstruction of the upper airway during sleep causing profound hypoxaemia: a neglected mechanism exacerbating chronic respiratory failure. Aust N Z J Med 1976;6:481–486. |
| 63. | Rapoport DM, Sorkin B, Garay SM, Goldring RM. Reversal of the “Pickwickian syndrome” by long-term use of nocturnal nasal-airway pressure. N Engl J Med 1982;307:931–933. |
| 64. | Sullivan CE, Berthon-Jones M, Issa FG. Remission of severe obesity–hypoventilation syndrome after short-term treatment during sleep with nasal continuous positive airway pressure. Am Rev Respir Dis 1983;128:177–181. |
| 65. | Banerjee D, Yee BJ, Piper AJ, Zwillich CW, Grunstein RR. Obesity hypoventilation syndrome: hypoxemia during continuous positive airway pressure. Chest 2007;131:1678–1684. |
| 66. | Laaban JP, Orvoen-Frija E, Cassuto D, Pascal S, Leger D, Basdevant A, Rochemaure J, Guy-Grand B. Mechanisms of diurnal hypercapnia in sleep apnea syndromes associated with morbid obesity. Presse Med 1996;25:12–16. |
| 67. | Shivaram U, Cash ME, Beal A. Nasal continuous positive airway pressure in decompensated hypercapnic respiratory failure as a complication of sleep apnea. Chest 1993;104:770–774. |
| 68. | Krieger J, Weitzenblum E, Monassier JP, Stoeckel C, Kurtz D. Dangerous hypoxaemia during continuous positive airway pressure treatment of obstructive sleep apnoea. Lancet 1983;2:1429–1430. |
| 69. | Mokhlesi B. Positive airway pressure titration in obesity hypoventilation syndrome: continuous positive airway pressure or bilevel positive airway pressure. Chest 2007;131:1624–1626. |
| 70. | Schafer H, Ewig S, Hasper E, Luderitz B. Failure of CPAP therapy in obstructive sleep apnoea syndrome: predictive factors and treatment with bilevel-positive airway pressure. Respir Med 1998;92:208–215. |
| 71. | Ellis ER, Grunstein RR, Chan S, Bye PT, Sullivan CE. Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 1988;94:811–815. |
| 72. | Piper AJ, Sullivan CE. Effects of short-term NIPPV in the treatment of patients with severe obstructive sleep apnea and hypercapnia. Chest 1994;105:434–440. |
| 73. | Waldhorn RE. Nocturnal nasal intermittent positive pressure ventilation with bi-level positive airway pressure (BiPAP) in respiratory failure. Chest 1992;101:516–521. |
| 74. | 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. |
| 75. | Heinemann F, Budweiser S, Dobroschke J, Pfeifer M. Non-invasive positive pressure ventilation improves lung volumes in the obesity hypoventilation syndrome. Respir Med 2007;101:1229–1235. |
| 76. | Masa JF, Celli BR, Riesco JA, Sanchez de Cos J, Disdier C, Sojo A. Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest 1997;112:207–213. |
| 77. | Kimura H, Tatsumi K, Kunitomo F, Okita S, Tojima H, Kouchiyama S, Masuyama S, Shinozaki T, Mikami M, Watanabe S, et al. Obese patients with sleep apnea syndrome treated by progesterone. Tohoku J Exp Med 1988;156:151–157. |
| 78. | Marrone O, Milone F, Coppola P, Oddo S, Giannone G, Macaluso C, Bonsignore G. Effects of almitrine bismesylate on nocturnal hypoxemia in patients with chronic bronchitis and obesity. Eur J Respir Dis Suppl 1986;146:641–648. |
| 79. | Poulter NR, Chang CL, Farley TM, Meirik O. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet 1999;354:1610. |
| 80. | Douketis JD, Julian JA, Kearon C, Anderson DR, Crowther MA, Bates SM, Barone M, Piovella F, Turpie AG, Middeldorp S, et al. Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study. J Thromb Haemost 2005;3:943–948. |
| 81. | O'Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 1999;159:1477–1484. |
| 82. | 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. |
| 83. | Sugerman HJ, Fairman RP, Sood RK, Engle K, Wolfe L, Kellum JM. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr 1992;55:597S–601S. |
| 84. | Verse T. Bariatric surgery for obstructive sleep apnea. Chest 2005;128:485–487. |
| 85. | DeMaria EJ, Portenier D, Wolfe L. Obesity surgery mortality risk score: proposal for a clinically useful score to predict mortality risk in patients undergoing gastric bypass. Surg Obes Relat Dis 2007;3:134–140. |
| 86. | Squadrone V, Coha M, Cerutti E, Schellino MM, Biolino P, Occella P, Belloni G, Vilianis G, Fiore G, Cavallo F, et al. Continuous positive airway pressure for treatment of postoperative hypoxemia: a randomized controlled trial. JAMA 2005;293:589–595. |
| 87. | Ebeo CT, Benotti PN, Byrd RP Jr, Elmaghraby Z, Lui J. The effect of bi-level positive airway pressure on postoperative pulmonary function following gastric surgery for obesity. Respir Med 2002;96:672–676. |
| 88. | El-Solh AA, Aquilina A, Pineda L, Dhanvantri V, Grant B, Bouquin P. Noninvasive ventilation for prevention of post-extubation respiratory failure in obese patients. Eur Respir J 2006;28:588–595. |
| 89. | Huerta S, DeShields S, Shpiner R, Li Z, Liu C, Sawicki M, Arteaga J, Livingston EH. Safety and efficacy of postoperative continuous positive airway pressure to prevent pulmonary complications after Roux-en-Y gastric bypass. J Gastrointest Surg 2002;6:354–358. |
| 90. | Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693. |
| 91. | Pillar G, Peled R, Lavie P. Recurrence of sleep apnea without concomitant weight increase 7.5 years after weight reduction surgery. Chest 1994;106:1702–1704. |
| 92. | Lee WY, Mokhlesi B. Diagnosis and management of obesity hypoventilation syndrome in the intensive care unit. Crit Care Clin (In press.) |
| 93. | Redolfi S, Corda L, La Piana G, Spandrio S, Prometti P, Tantucci C. Long-term non-invasive ventilation increases chemosensitivity and leptin in obesity–hypoventilation syndrome. Respir Med 2007;101:1191–1195. |
| 94. | Piper AJ, Wang D, Yee BJ, Grunstein RR. Randomised trial of CPAP vs bilevel support in the initial management of patients with obesity hypoventilation syndrome. Sleep Biol Rhythms 2006;4:A11. |
| 95. | 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 (In press) |
| 96. | 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. |
| 97. | Reeves-Hoche MK, Meck R, Zwillich CW. Nasal CPAP: an objective evaluation of patient compliance. Am J Respir Crit Care Med 1994;149:149–154. |
| 98. | Rauscher H, Formanek D, Popp W, Zwick H. Self-reported vs measured compliance with nasal CPAP for obstructive sleep apnea. Chest 1993;103:1675–1680. |
| 99. | Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, Redline S, Henry JN, Getsy JE, Dinges DF. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887–895. |
| 100. | Rodriguez P, Lellouche F, Aboab J, Buisson CB, Brochard L. Transcutaneous arterial carbon dioxide pressure monitoring in critically ill adult patients. Intensive Care Med 2006;32:309–312. |
| 101. | Senn O, Clarenbach CF, Kaplan V, Maggiorini M, Bloch KE. Monitoring carbon dioxide tension and arterial oxygen saturation by a single earlobe sensor in patients with critical illness or sleep apnea. Chest 2005;128:1291–1296. |