Obesity Hypoventilation Syndrome

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Chapter 62 Obesity Hypoventilation Syndrome

Gimbada B. Mwenge, Daniel Rodenstein

Obesity hypoventilation syndrome is a disorder characterized by the presence of daytime compensated respiratory acidosis (i.e., hypercapnia with normal pH and increased serum bicarbonate), in patients in whom no cause of ventilatory failure can be identified. These patients cannot ensure a normal minute ventilation even in the resting state, although clinical evaluation will rule out disorders associated with decreased muscle force (neuromuscular diseases), abnormal muscle geometry (e.g., kyphoscoliosis), severe airway obstruction and abnormal ventilation-perfusion relationships (e.g., chronic obstructive pulmonary disease [COPD], emphysema), or parenchymal abnormalities (e.g., interstitial lung diseases). In these patients, with performance of a respiratory maneuver consisting of serial deep inspirations, subsequently the arterial carbon dioxide tension (PaCO2) normalizes, and in those in whom hypoxia is present, oxygen saturation (SaO2) rises by 4% to 6% in less than 2 minutes. Of note, however, they do not sustain adequate minute ventilation and remain hypercapnic, with the kidneys compensating to maintain a normal pH. Another clinical element quite evident is that such persons are obese, frequently morbidly obese, with body mass index (BMI) values in excess of 35 kg/m2. It is the association of pathologic obesity and daytime hypercapnia that defines the obesity hypoventilation syndrome.

When these patients are studied in a sleep laboratory, it becomes clear that they are afflicted with some form of sleep-disordered breathing pattern. The vast majority of patients have a moderate to severe form of obstructive sleep apnea (OSA), with a minority showing no obstructed breathing but simply sleep-related hypoxia and hypercapnia (long periods of SaO2 below 90% and an increase in PaCO2 of about 10 mm Hg developing overnight). The diagnosis of obesity hypoventilation syndrome can be reached with certainty only when other causes of daytime hypercapnia have been excluded.

Epidemiology

The prevalence of obesity hypoventilation syndrome in the general population remains unknown. In the United States, it has been estimated to be between 0.15% and 0.3%. A study conducted in obese hospitalized patients with a BMI greater than 35 kg/m2 found a prevalence of 31%. Among patients with OSA, previous European studies (France, Italy, Greece, and Spain) found occurrence rates for obesity hypoventilation syndrome of 9% to 17%. Studies from the United States found a prevalence of greater than 20% in this patient group.

The gender ratio for obesity hypoventilation syndrome remains uncertain: Even if the prevalence seems to be higher in men, some studies found a higher proportion of the cases in women. All reported data come from selected cohorts of hospitalized patients or from sleep laboratories.

Risk Factors

Several conditions seem to predispose an obese person to development of the obesity hypoventilation syndrome. Undisputedly, in comparison with patients with OSA, patients diagnosed with this syndrome seem to be more obese, and they have more severe OSA. The main cause of obesity is well recognized to be an excess of food intake in relation to the energy expenditure requirements of the organism, resulting in the constitution of an energy stock essentially in the form of fat deposits. According to worldwide epidemiologic data, the prevalence of obesity is increasing everywhere, and this trend seems to be related essentially to a rapid change in eating habits, themselves influenced by technologic changes and food industry policies. Whether this reflects an improvement in the standard of living is a matter of debate.

The health consequences of obesity should prompt implementation of educational strategies to promote adequate behavioral changes in eating habits. Nevertheless, at the individual level, genetic factors may have an influence on the development of obesity, depending on the balance between what can be termed “catabolic” and “anabolic” genes. More than 250 genes have been identified that have a more or less important influence on the final handling of the energetic balance. The clinical importance of each genetic variant, however, is not yet well appreciated. Only a few monogenetic causes of obesity have been described in humans, the best example being mutations in the gene coding for the melanocortin 4 receptor. It has to be stressed, however, that obesity will not develop if access to food is compromised, or if energy expenditure exceeds energy absorption.

An apnea-hypopnea index (AHI) greater than 50, as measured by the number of apneic or hypopneic episodes per hour of sleep, also seems to be a risk factor for obesity hypoventilation syndrome, because 25% of patients with such AHIs in several studies had the syndrome. Oxygen saturation nadir levels below 60% during polysomnography and moderate to severe restriction found on pulmonary function testing also are predictors for the syndrome, with odds ratios of 4 and 10, respectively. Finally, some studies found that patients with obesity hypoventilation syndrome had greater neck, waist, and hip circumferences and a larger waist-to-hip ratio than their counterparts with OSA.

Pathophysiology

Obese patients, both eucapnic and hypercapnic, have significant reductions in functional residual capacity and expiratory reserve volume with preservation of inspiratory capacity and often normal or slightly reduced total lung capacity. But obesity is not, however, the only determinant of hypoventilation, because only a third of morbidly obese persons develop hypercapnia. Some differences between eucapnic obese and hypercapnic subjects have been recognized and are summarized next.

Reduced Muscle Strength

The maximal inspiratory and expiratory pressures are normal in eucapnic morbidly obese patients but may be reduced in patients with obesity hypoventilation syndrome, although this is not a universal finding.

Central Respiratory Drive

Many studies found that patients with obesity hypoventilation syndrome do not hyperventilate to the same degree as morbidly obese patients without the syndrome when rebreathing CO2. This deficit corrects in most patients after normalization of PaCO2. In patients with severe OSA but without hypercapnia, the hypercapnic ventilatory response does not change with continuous positive airway therapy (CPAP). The reversibility of the blunted central drive suggests that this is a secondary phenomenon of the syndrome (and necessary for its persistence), but not the origin of it.

Obstructive Sleep Apnea

OSA may play a role in the pathogenesis of chronic hypercapnia in those patients, because in most cases, treatment of OSA corrects the hypercapnia. Indeed, to compensate for the effect of intermittent periodic breathing and resultant acute hypercapnia, normal subjects as well as patients with OSA will increase their tidal volume in the first breath after an apnea (hyperventilation). With physiologic differences in ventilatory responses between subjects, however, an overload in CO2 could result. The duration of the apneas also could contribute: When apneic episode duration becomes three times longer than the breathing interval, CO2 tends to accumulate despite maximal tidal volume, because there is insufficient time for adequate hyperventilation events (Figure 62-1). In addition, hypercapnia could blunt the ventilatory responses: The initial ventilation after an apneic episode is directly related to the volume of CO2 loaded during the preceding respiratory event and thus represents an index of CO2 ventilatory response. Hypercapnic patients demonstrated depression of this index of ventilatory compensation compared with that in eucapnic patients. It has been shown that the apnea-to-interapnea duration ratio is greater in hypercapnic patients than in eucapnic patients.

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Figure 62-1 Five-minute tracing from a diagnostic polysomnography study. Top to bottom: Two electrooculograms (EOG); chin electromyogram (EMG1); three electroencephalograms (C3-A2, C4-A1, C3-O1); electrocardiogram (ECG); leg movement electromyograms (EMG2, EMG3); snoring recordings (PHONO); oronasal flow with a thermocouple (NAF1); nasal flow (NAF2P); abdominal and thoracic movement from inductive plethysmographic bands (VAB, VTH); and oxygen saturation measurement with pulse oximetry (SaO2). The subject is in stage 2 non-REM sleep. Note the absence of nasal flow and persistent abdominal and thoracic movements with falls in oxygen saturation, with successive obstructive apneas ending with loud snoring and leg movements (with one exception). REM, rapid eye movement.

One study also has shown impaired CO2 homeostasis after respiratory events may be mediated by opioids or opioid receptors, because endorphin blockade changed this pattern. Increased cerebrospinal fluid beta-endorphin activity with return to normal values has been reported in subjects with OSA. This finding could explain hypercapnia on awakening after a night full of apneic episodes. To understand why in a period of wakefulness free of apnea the PaCO2 does not normalize, the role of the renal system has to be considered. Hypercapnia leads to respiratory acidosis, which activates the process of renal compensation.

To elucidate the mechanisms that are involved in the development of hypercapnia in patients with OSA, Norman and co-workers have proposed, using a computer model, some hints for prediction of the transition from acute hypercapnia during sleep-disordered breathing (apnea, hypopnea, and hypoventilation) to chronic daytime hypercapnia. In their model, when the ventilatory CO2 response and renal HCO3− excretion were normal, increases in PaCO2 and HCO3− did not develop. The bicarbonate excretion during the day compensated for that retained during the night. When CO2 ventilatory response was very low, however, the model demonstrated a modest rise in PaCO2 and HCO3− measured during the awake state over multiple days. Similarly, when renal HCO3− excretion rate was lowered to simulate chloride deficiency, the model demonstrated a modest rise in daytime PaCO2 and HCO3−. The combination of low CO2 response and low renal HCO3− excretion rate produced a synergistic effect on the degree of elevation of daytime PaCO2. These workers suggested that hypercapnia results from an imbalance between the period of CO2 loading (short = apnea or hypopnea; long = hypoventilation) and inadequate compensation both during sleep and during the awake state. This pulmonary-renal interaction may contribute to the development and perpetuation of chronic daytime hypercapnia, which will lead to a blunted respiratory drive for the next sleep cycle (Figure 62-2).

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Figure 62-2 Schematic representations of the physiopathology of obesity hypoventilation syndrome. Respiratory events with the combination of low CO2 ventilatory response and low renal HCO3− excretion rate produce a synergistic effect on the degree of elevation of daytime PaCO2. Chronic hypercapnia will then lead to blunted ventilatory responses, possibly decreased diaphragmatic function, and decreased leptin response.

There is clearly a link between the pathogenesis of OSA and pure hypoventilation in patients with obesity hypoventilation syndrome. In their study, De Miguel Díez and colleagues provided ventilatory support to 12 patients with pure obesity hypoventilation syndrome (without sleep apnea), using noninvasive ventilation (NIV), for a minimum period of 1 year. After 3 months subsequent to discontinuation of NIV and disappearance of hypercapnia, 7 patients had developed obstructive sleep apnea syndrome. These data suggest that impairment of the ventilatory drive caused by compensated respiratory acidosis may potentially lead the switch from apnea-hypopnea syndrome to pure obesity hypoventilation syndrome.

Neurohormonal Response (Leptin Resistance)

Leptin is a protein released by adipose tissue. Its functions are to reduce appetite and increase energy expenditure. In obesity, some studies have found high blood levels of leptin but without the expected physiologic effects, suggesting the presence of so-called leptin resistance. Animal studies have shown that this protein is a potent stimulus of ventilation, and absence of or reduction in its action may result in hypoventilation. Serum levels of leptin are decreased or normal after CPAP treatment in patients with OSA. A hypothesis for this association is that the apnea and hypopnea could be the cause of the elevation of leptin, rather than the result. Leptin levels are twice as high in patients with obesity hypoventilation syndrome as in patients with similar degrees of obesity and similar AHI values. Leptin levels can be reduced with NIV or weight loss. All of these observations have led to the idea that resistance to leptin may be the cause of obesity hypoventilation syndrome. A recent study, however, found opposite results: Those patients with the syndrome not associated with a significant number of apneic and hypopneic episodes have lower leptin levels than those obese patients with the same number of obstructive events without daytime hypercapnia and obesity, and leptin levels increased with treatment with NIV. More studies have to be performed to clarify those findings. Clearly, as yet, no comprehensive picture of the neurohumoral interactions in obesity hypoventilation syndrome has emerged.

Clinical Features

The following clinical features have been found in a systematic review of the literature including a significant number of patients. Patients typically are diagnosed in the sixth decade of life and prevalence is slightly higher in men (60%). Compared with patients with OSA, patients with obesity hypoventilation syndrome are severely obese (mean, 44 kg/m2; range, 35 to 56 kg/m2). Up to 90% of these patients have OSA, with an AHI in the severe range (mean, 66; range, 20 to 100). Subjects with obesity hypoventilation syndrome are sleepier than those with OSA (on the Epworth sleepiness scale, a score of 14.6 ± 4.9, versus 12.5 ± 4.6). The impact of this excessive sleepiness has the same consequences, with decrements in work performance, concentration lapses, inattention, and increased reaction time. Nocturnal and daytime hypoxemia also characterize obesity hypoventilation syndrome. Depending on the studies, the mean reported daytime PaO2 is 53 mm Hg (47 to 74 mm Hg). Finally, the nadir of oximetry-measured oxygen saturation (SpO2) during sleep often is below 60%.

Diagnosis

History

Most patients with obesity hypoventilation syndrome will have some daytime respiratory complaints (dyspnea) and some degree of excessive daytime sleepiness. They often have comorbid illnesses at the time of diagnosis, such as diabetes and hypertension. All other complaints also are seen in typical eucapnic patients with OSA, including loud snoring, nocturnal choking episodes with witnessed apneas, and excessive daytime sleepiness, nycturia, mood disturbance, and morning headaches. The diagnosis usually is made by a sleep specialist or a respiratory physician. Alternatively, in patients previously treated for OSA successfully, recurrence of symptoms can suggest a shift toward obesity hypoventilation syndrome. Frequently, patients are diagnosed after an episode of acute respiratory failure with admission to intensive care unit.

Physical Examination

Physical examination in both eucapnic and hypercapnic patients with obesity hypoventilation syndrome usually reveals a BMI higher than 40 kg/m2 and a neck circumference greater than 42 cm in men and 40 in women. The oral examination shows a large tongue with a crowded oropharynx (Mallampati score IV; Friedman tongue position index of 3 or 4). Few specific findings have been recognized to distinguish obesity hypoventilation syndrome from OSA: Abnormal oxygen saturation (SpO2) detected by finger pulse oximetry during the awake state also should lead clinicians to exclude the syndrome in patients with OSA, because hypoxemia during the awake state is not common in these patients.

Patients with obesity hypoventilation syndrome may present with signs of cor pulmonale: a prominent pulmonic component of the second heart sound on cardiac auscultation, lower extremity edema, injected sclera (thought to be related to elevated PaCO2 and cerebral vasodilatation), hepatomegaly, and prominent jugular veins.

Blood Gas Analysis and Serum Blood Chemistry

Elevated serum venous bicarbonate level has been suggested as an effective screening tool. Of patients with serum bicarbonate levels greater than 27 mmol/L and clinical obesity (BMI higher than 30 kg/m2), 38% had obesity hypoventilation syndrome in one study. If obesity was severe and lung function showed restriction and severe OSA, the prevalence of obesity hypoventilation syndrome jumped to 56%.

Hypothyroidism is a rare occurrence, but it may be worth excluding with a thyroid-stimulating hormone (TSH) challenge test.

“Awake” (daytime) hypercapnia (PaCO2 greater than 45 mm Hg) in arterial blood is a defining criterion for the diagnosis and frequently is accompanied by daytime hypoxia.

Sleep Laboratory Diagnosis

Sleep-disordered breathing can take either of two forms; the most common type is OSA, and the second one is central hypoventilation. Polysomnographic evaluation shows either a typical OSA pattern or periods of fall in SaO2 in REM stages alone (Figure 62-3) or throughout the entire sleep period (Figure 62-4). In many cases, sleep-disordered breathing is seen throughout sleep, with steep falls in saturation in non-REM sleep and much steeper falls in the REM stage (see Figure 62-4).

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Figure 62-3 Top to bottom: The first horizontal panel shows a graph of the wake and sleep data: A, awake state; R, REM sleep; 1, 2, 3, 4, non-REM sleep stages; U, unknown stage; M, movement. The next panels show arousal index (ArI), index of periodic leg movements (PLMSI), body position (with the supine position indicated as 0), snoring as a percentage of sleep time, apnea-hypopnea index (AHI), desaturation index (DI) (defined as the number of 4% or greater falls in oxygen saturation [SaO2] per hour of sleep), and heart rate. Of note, apneas and hypopneas lead to falls in oxygen saturation, but these falls are much steeper during REM sleep. REM, rapid eye movement; TST, total sleep time.

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Figure 62-4 Note low SaO2 throughout the night and deeper falls in SaO2 related to the period of REM sleep. For abbreviations, see Figure 62-3.

In some patients, REM sleep may even be completely absent (Figure 62-5).

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Figure 62-5 Note low SaO2 throughout the night, with cyclic falls and recoveries, and the almost complete absence of REM sleep. For abbreviations, see Figure 62-3.

Spirometry

The most predictable and pronounced effects of obesity on lung function are decrease in functional residual capacity (FRC) and in expiratory reserve volume (ERV) associated with the closure of peripheral lung units and ventilation-to-perfusion ratio abnormalities that appear when the subject is lying down. When obese persons achieve significant weight loss, FRC increases. In patients with obesity hypoventilation syndrome, total lung capacity (TLC) is normal or mildly decreased, whereas ERV and FRC are reduced, compared with values in eucapnic patients, and these changes are more evident in patients with obesity hypoventilation syndrome than in eucapnic patients, even at similar BMI.

Chest Radiography

Plain chest radiography shows no special features. Nevertheless, this imaging study is recommended to exclude interstitial lung disease and chest wall deformities (severe kyphoscoliosis), or diaphragmatic paralysis.

Cardiac Echography

In cases of cor pulmonale, echocardiography may confirm the diagnosis and is useful for follow-up evaluation.

Clinical Course: Morbidity and Mortality

Obesity in itself does not result in a higher rate of morbidity and mortality in intensive care units (ICUs). This has been demonstrated in a matched-patient study that found that BMI did not have a significant impact on mortality in this sample.

Patients with obesity hypoventilation syndrome are heavy users of health care resources for several years before the evaluation and treatment of their sleep-related breathing disorder, and a substantial reduction in days hospitalized is achieved once treatment is instituted. Nowbar and associates showed a clear increase in mortality after hospital discharge in the follow-up evaluation for obesity hypoventilation syndrome compared with simple obesity.

The most common consequences in obesity hypoventilation syndrome include polycythemia, hypothyroidism, pulmonary hypertension, right-sided heart failure, and acute respiratory failure.

MacGregor and associates reported a high level of mortality, including sudden death, in patients with obesity hypoventilation syndrome and a subsequent reduction in mortality with the institution of mechanical ventilation. These findings were reinforced by the study by Budweiser and colleagues that demonstrated improvement of gas exchange and lung function in obesity hypoventilation syndrome after initiation of NIV. These workers also underlined the relationship between a poor survival and the presence of hypoxemia, low pH and elevated inflammation markers.

Treatment

Weight Reduction

The ideal treatment is weight loss. Restoration of a normal weight reverses respiratory failure, pulmonary hypertension, and sleep-related disordered breathing. The problem is that it is difficult to achieve and maintain significant weight loss in these patients. Bariatric surgery appears to be the most effective means to achieve long-term reduction in body weight. This is a treatment reserved for a minority of subjects, however, owing to increased surgical morbidity and mortality of patients with obesity hypoventilation syndrome. The perioperative mortality rate for this procedure is between 0.5% and 1.5%. The independent risk factors associated with mortality are intestinal leaks and pulmonary embolism. Ideally, patients with obesity hypoventilation syndrome should be supported with CPAP therapy or NIV before undergoing surgical intervention, in order to decrease perioperative morbidity and mortality. Moreover, CPAP or NIV therapy should be reinitiated immediately after extubation, to avoid postoperative respiratory failure.

Reversal of Sleep-Disordered Breathing

Noninvasive Ventilation

The efficiency of NIV has been extensively studied. It can be expected to produce a successful clinical response, as has been shown in many diseases and conditions associated with hypercapnia (kyphoscoliosis, central alveolar hypoventilation). NIV provides significant long-term improvement in PaO2 and PaCO2 and relief of subjective sleepiness and dyspnea.

NIV often is used as second-line treatment after a trial with CPAP, which may be warranted owing to lack of adherence to CPAP therapy, lack of improvement in hypercapnia, or the persistence of hypoxemia despite CPAP. It also should be considered in patients with obesity hypoventilation syndrome who experience an episode of acute-on-chronic respiratory failure and in patients who have obesity hypoventilation syndrome without OSA.

Continuous Positive Airway Pressure

CPAP treatment improves AHI, REM duration, arousal indices, and nocturnal oxygen saturation. In some subjects, however, nocturnal desaturation continues despite the treatment. When evaluated in various cohorts of selected patients without severe hypoxia, CPAP alone produced a satisfactory response in 80% of patients, the others needing NIV. Although CPAP and NIV are widely used for treatment of obesity hypoventilation syndrome, no randomized controlled trial has been conducted in unselected patients, to determine if one of these treatments is more effective or efficient, or for any comparison with weight loss. Also lacking are studies systematically evaluating longer-term response (6 months) of patients with obesity hypoventilation syndrome placed on CPAP, so it is unclear what impact this therapy has on outcomes such as hospitalization and survival.

Thus far, no study has yielded a valid method for predicting success or failure with CPAP, thereby predicting the need for NIV. Until good data allow a reasoned choice, the best option appears to be a trial of CPAP. If sleep-disordered breathing and respiratory acidosis are not corrected, a change to NIV is warranted.

Tracheostomy

Performance of a tracheostomy bypasses the upper airway, with consequent reduction in risk for obstructive events. In patients with OSA, tracheostomy was shown to be an effective treatment alternative despite the presence of hypercapnia. For various reasons, however, it is not recommended in most patients with obesity hypoventilation syndrome. Tracheostomy is challenging in the morbidly obese. Complications have occurred with use of both the surgical and percutaneous approaches. Complications most frequently reported with percutaneous tracheostomy are need to abort the procedure, accidental extubation, need for conversion to surgical tracheostomy, paratracheal placement, development of pneumothorax, major bleeding (requiring blood product transfusion or surgical intervention), hypoxia, minor bleeding (requiring pressure dressing or suturing), subcutaneous emphysema, transient hypotension, tube obstruction, malpositioning of the tracheostomy tube after being dislodged, and death. Because CPAP and NIV are effective in most cases, tracheostomy is certainly not a first choice for management of obesity hypoventilation syndrome.

Pharmacotherapy

Very few drug trials have been conducted in patients with obesity hypoventilation syndrome. A recent study by Raurich and co-workers in Spain, performed in 25 patients with obesity hypoventilation syndrome, investigated the relationship between CO2 response, BMI, and plasma bicarbonate concentration and the effect of acetazolamide on bicarbonate concentration and CO2 response in ventilated patients with acute respiratory failure. These workers found that the addition of acetazolamide decreased bicarbonate concentration and increased CO2 response. They suggest that this treatment could be used as a complement in ventilation.

Conclusions

Obesity hypoventilation syndrome seems to develop only in the presence of massive obesity and represents one of the most serious respiratory complications of obesity. This syndrome is both preventable and treatable, and the treatment apparently is independent of the maintenance or the loss of the excessive weight. If left undiagnosed and untreated, obesity hypoventilation syndrome leads to severe health consequences. Unfortunately, this clinical entity is underdiagnosed—it remains primarily a subject of interest to a small number of physicians puzzled by the interrelation between sleep and breathing, whereas it remains hidden behind obesity for the vast majority of physicians. The increase in the worldwide prevalence of obesity will require a dedicated educational effort by health care professionals to make this disease better known. Otherwise, patients will continue being diagnosed in the ICU setting, once a first episode or several episodes of acute respiratory failure have precipitated a life-threatening crisis necessitating emergency care.

Controversies and Pitfalls

Although considerable advances have added to the current understanding of how the obesity hypoventilation syndrome develops and becomes established, a vast amount of uncertainty remains regarding its clinical presentation and consequences. Some of the unresolved issues are as follows:

• Is the obesity hypoventilation syndrome just a particular form of obesity, so that losing weight would be enough to cure it?

• Does the obesity hypoventilation syndrome prevent weight loss via excessive daytime sleepiness, decrease in energy consumption, and exacerbated hunger sensation?

• What is the simpler and best screening method to identify patients at risk and to prompt an adequate diagnostic process?

• Is polysomnography necessary to manage patients with obesity hypoventilation syndrome?

• Is the respiratory treatment of the sleep-related causes of obesity hypoventilation syndrome (i.e., CPAP for the apnea-hypopnea syndrome or NIV for sleep-related hypoventilation) enough to protect the patient’s health, or is weight loss still a mandatory component of management?

• CPAP is an efficient therapy in many patients. A sizable number, however, do not respond to this intervention. What are the predictive factors that could rapidly identify such nonresponders?

• In patients needing NIV, how many can revert to a simpler CPAP treatment?

• In patients needing NIV, when is a shift to CPAP advisable?

• What is the cost-utility ratio of CPAP and NIV in OHS?

• CPAP or NIV treatment seems to decrease mortality, but this has been assessed in a limited number of patients. Long-term follow-up studies in larger cohorts are needed to confirm this major outcome and to determine the confounding effect of persistent obesity on survival.

Suggested Readings

Banerjee D, Yee BJ, Piper AJ, et al. Obesity hypoventilation syndrome: hypoxemia during continuous positive airway pressure. Chest. 2007;131:1678–1684.

Berg G, Delaive K, Manfreda J, et al. The use of health-care resources in obesity-hypoventilation syndrome. Chest. 2001;120:377–383.

Budweiser S, Riedl SG, Jorres RA, et al. Mortality and prognostic factors in patients with obesity-hypoventilation syndrome undergoing noninvasive ventilation. J Intern Med. 2007;261:375–383.

Chouri-Pontarollo N, Borel JC, Tamisier R, et al. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: impact of noninvasive ventilation. Chest. 2007;131:148–155.

De Miguel Díez J, De Lucas Ramos P, Pérez Parra JJ, et al. [Analysis of withdrawal from noninvasive mechanical ventilation in patients with obesity-hypoventilation syndrome. Medium term results.]. Arch Bronconeumol. 2003;39:292–297.

Lumachi F, Marzano B, Fanti G, et al. Hypoxemia and hypoventilation syndrome improvement after laparoscopic bariatric surgery in patients with morbid obesity. In Vivo. 2010;24:329–331.

MacGregor MI, Block AJ, Ball WCJr. Topics in clinical medicine: serious complications and sudden death in the Pickwickian syndrome. Johns Hopkins Med J. 1970;126:279–295.

Marien H, Rodenstein D. Morbid obesity and sleep apnea. Is weight loss the answer? Clin Sleep Med. 2008;4:339–340.

Masa JF, Celli BR, Riesco JA, et al. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest. 2001;119:1102–1107.

Norman RG, Goldring RM, Clain JM, et al. Transition from acute to chronic hypercapnia in patients with periodic breathing: predictions from a computer model. J Appl Physiol. 2006;100:1733–1741.

Nowbar S, Burkart KM, Gonzales R, et al. Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med. 2004;116:1–7.

Pérez de Llano LA, Golpe R, Ortiz Piquer M, et al. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest. 2005;128:587–594.

Raurich JM, Rialp G, Ibáñez J, et al. Hypercapnic respiratory failure in obesity-hypoventilation syndrome: CO2 response and acetazolamide treatment effects. Respir Care. 2010;55:1442–1448.

Trakada GP, Steiropoulos P, Nena E, et al. Prevalence and clinical characteristics of obesity hypoventilation syndrome among individuals reporting sleep-related breathing symptoms in northern Greece. Sleep Breath. 2010;14:381–386.

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