INTRODUCTION — Obesity Hypoventilation Syndrome (OHS; "Pickwickian syndrome") is defined as the presence of awake alveolar hypoventilation (arterial carbon dioxide tension [PaCO2] >45 mmHg) in an obese individual (body mass index ≥30 kg/m2) which cannot be attributed to other conditions associated with alveolar hypoventilation (eg, neuromuscular disorders) [1-3].
The pathogenesis of OHS is reviewed here. Clinical manifestations, diagnosis, and treatment are discussed separately. (See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome" and "Treatment and prognosis of the obesity hypoventilation syndrome" and "Noninvasive positive airway pressure therapy for the obesity hypoventilation syndrome".)
EPIDEMIOLOGY — Prevalence estimates for OHS are inaccurate and vary significantly due to differences in disease definition, population studied, and methods of sample acquisition.
●General population – Estimates based on rates of obesity and obstructive sleep apnea (OSA) in the community suggest 0.15 to 0.3 percent of the adult population in the United States are likely to have OHS [1].
●Obese population – The prevalence of OHS increases as body mass index (BMI) rises [4,5]. In several retrospective studies among patients with OSA, the prevalence of OHS in those with a BMI of 30 to 35 kg/m2 is 8 to 12 percent, higher among those with a BMI ≥40 kg/m2 (18 to 31 percent) and those with a BMI ≥50 kg/m2 (50 percent) [1,5-9].
●OSA – Retrospective studies report a rate of 16 percent among those referred to sleep center with symptoms of OSA, higher (22 percent) if patients were obese, or have severe OSA (eg, apnea hypopnea index >60 events per hour; 20 to 30 percent) [5,6,10].
●Bariatric surgery – Prevalence rates vary from 8 to 65 percent in bariatric surgical patients [11-13].
●Hospitalized patients – In a study of hospitalized patients with a BMI >35 kg/m2, the prevalence of OHS was 31 percent [4]. In a single center study, 8 percent of ICU admissions fulfilled the criteria for OHS [14].
●Chronic hypoxemia – In another study of patients with obesity with chronic hypoxemia, 51 percent were found to have OHS [15].
Ethnic factors also affect prevalence rates. In Japanese patients presenting for investigation of OSA, 2.3 percent were found to have OHS [16] compared with 20 percent of predominantly African-American patients evaluated at a United States sleep center [6]. However, Asian-Americans may develop OHS at a lower BMI than non-Asian Americans, possibly due to cephalometric differences [7,16-19].
PATHOGENESIS — Obesity (body mass index [BMI]> 30 kg/m2), in particular, severe obesity (BMI >50 kg/m2), is the major risk factor for OHS [1,5-9,20]. Obesity induces increased demand on the respiratory system that triggers compensatory mechanisms to maintain adequate ventilation (ie, eucapnia; partial arterial pressure of carbon dioxide [PaCO2 <45 mmHg]). It is thought that OHS develops due to the failure of such compensatory mechanisms resulting in hypoventilation and hypercapnia (PaCO2 ≥45 mmHg) [21].
A complex interaction between the following factors is likely involved in the pathogenesis of OHS (table 1 and algorithm 1) [21]:
●Sleep disordered breathing (SDB)
●Altered pulmonary mechanics
●Impaired ventilatory control
●Increased carbon dioxide production
A "pre-OHS" state in patients with class 2 or 3 obesity who have a normal daytime PaCO2 but an elevated base excess or bicarbonate has been proposed [22]. A European Respiratory Taskforce addressing diagnostic and therapeutic standards in central sleep breathing disturbances has put forward a framework for defining obesity-related hypoventilation, which incorporates this concept [2]. In this framework:
●Stages I and II obesity-related hypoventilation incorporates obese individuals with intermittent sleep hypercapnia but a normal awake PaCO2. Serum bicarbonate in these stages are <27 mmol/L or >27 mmol/L, respectively.
●Stages III and IV describe OHS individuals, with Stage IV representing those OHS individuals with cardiometabolic comorbidities while Stage III OHS do not.
Further studies are needed to understand the processes that influence progression of obesity to OHS.
Sleep disordered breathing — The role of SDB in the pathogenesis of OHS is supported by the following observations:
●The majority of patients with OHS have concurrent obstructive sleep apnea (OSA) while pure sleep hypoventilation alone (nonobstructive events) is present in around 10 percent of individuals [7,23-25]. Ninety percent of patients with OHS have at least mild OSA (apnea-hypopnea index [AHI] >5 events per hour), with severe disease (AHI >30 events per hour) seen in 70 percent [26]. Most studies have examined mechanisms at play in patients with OHS and OSA and it is presumed that the same mechanisms are likely contributing in those with OHS and sleep hypoventilation. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
●Treatment of the nocturnal SDB usually with positive airway pressure or rarely tracheostomy, also treats/eliminates OHS [17,27-29]. (See "Management of obstructive sleep apnea in adults".)
In addition, although other obesity-related mechanisms (eg, altered mechanics and impaired ventilatory control) play a role in promoting hypoventilation during wakefulness, changes in gas exchange are most prominent during sleep, further emphasizing the contribution of SDB to the pathogenesis of OHS.
Reduced nocturnal carbon dioxide clearance — The mechanism of reduced nocturnal carbon dioxide (CO2) clearance is best studied in patients with OSA [30-35]. During obstructive apneic or hypopneic events, the partial arterial pressure of carbon dioxide (PaCO2) rises (figure 1). Patients with OSA who do not have OHS (ie, eucapnic OSA) are able to normalize their PaCO2 between such respiratory events. In contrast, OHS patients with OSA have reduced ventilation for longer periods between events, so that CO2 is not adequately eliminated (ie, hypercapnic acidosis develops) [30,31]. The renal system responds by retaining bicarbonate to buffer the falling pH [32,33]. If the renal system cannot adequately excrete the retained bicarbonate before the next sleep period, a gradual accumulation of serum bicarbonate occurs [33]. Raised serum bicarbonate levels will blunt the ventilatory response to additional rises in CO2 (ie, "won't breathe"), and ultimately results in the development of chronic alveolar hypoventilation as evidenced by a compensated respiratory acidosis during awake periods [34].
Nocturnal hypoxemia — In addition to awake and sleep hypercapnia, individuals with OHS exhibit more severe nocturnal hypoxemia during sleep than those with eucapnic OSA and/or obesity. The percentage of total sleep time spent with peripheral oxygen saturation levels <90 percent is strongly associated with the development of awake hypercapnia [20]. Sustained hypoxemia during external resistive loading in healthy individuals (which "mimics" obesity) was shown to result in delayed arousal during sleep [36], thereby promoting more prolonged periods of abnormal breathing. (See "Mechanisms, causes, and effects of hypercapnia", section on 'Oxygen-induced hypercapnia'.)
Impaired pulmonary mechanics
Abnormal spirometry — In patients with class 2 or 3 obesity, fat accumulation around the abdomen and chest wall contributes to a restrictive deficit which can impair ventilation. The inertial load of obesity itself and effect of gravity may further contribute to impaired alveolar ventilation, particularly during sleep [37-39]. Pulmonary function test findings in obesity are discussed separately. (See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome", section on 'Pulmonary function tests'.)
Ventilation/perfusion mismatching — Ventilation/perfusion (V/Q) mismatching in obese individuals may contribute to CO2 accumulation and hypoxemia in patients with OHS.
●Individuals with OHS adopt a pattern of breathing characterized by low tidal volume and increased respiratory rate, which increases anatomic dead space leading to CO2 accumulation [40]. (See "Mechanisms, causes, and effects of hypercapnia", section on 'Increased dead space'.).
●Obese individuals poorly ventilate (V) the lower lobes of their lungs, which may be due to diminished lung compliance, difficulty moving the ribcage and diaphragm, and closure of some alveoli prior to the end of expiration [41]. Obese individuals also have increased lower lobe perfusion (Q) due to increased pulmonary blood volume. The resulting V/Q mismatching (ie, areas that are underventilated relative to perfusion), leads to hypoxemia which can contribute to OHS. (See "Measures of oxygenation and mechanisms of hypoxemia".)
Reduced respiratory muscle strength — Obesity is associated with an increased work of breathing due to the increased load of obesity itself, a process that is exaggerated in the supine position during sleep [42]. Thus, respiratory muscles (eg, diaphragm and intercostal muscles) need to work harder to maintain eucapnia. Reduced respiratory muscle strength may contribute to the pathogenesis of OHS by contributing to hypoventilation (ie, "can't breathe"):
●Patients with OHS often have a modest reduction in respiratory muscle strength and endurance, which worsens in the supine position [42,43]. Although respiratory muscle impairment generally needs to be severe to cause clinically significant hypoventilation, modest impairment may be sufficient when other contributing factors such as excessive abdominal obesity, severe upper airway obstruction or low insulin-like growth factor 1 are present [44].
●Maximum voluntary ventilation (MVV), a marker of respiratory muscle strength, has been shown to be lower in patients with OHS compared with patients who have obesity but do not have OHS and negatively correlates with CO2 levels [38]. (See "Mechanisms, causes, and effects of hypercapnia", section on 'Decreased minute ventilation/global hypoventilation'.)
Impaired ventilatory control
Reduced neural drive — Neural drive is two to three times greater in patients with class 2 or 3 obesity without OHS compared to those of normal weight [42,45]. However, individuals with OHS lack this augmented drive [46-48].
Reduced ventilatory responsiveness — Hypoxemic and hypercapnic ventilatory responses (ie, the stimulation of ventilation by hypoxemia and hypercapnia) are typically reduced during sleep and may be exaggerated in patients with OHS, especially when patients are supine [22,39,44,49-51]. While the diminished ventilatory responsiveness to hypoxemia and hypercapnia appears to be an acquired, rather than a primary, defect, some evidence suggests that a reduced hypoxic ventilatory response exists in patients with obesity prior to the onset of overt OHS, thus some predisposition may exist [22]. In addition, studies show improved ventilatory responsiveness following effective treatment of sleep disordered breathing [49,52].
Leptin resistance — Leptin is an adipokine produced in adipose tissue that stimulates ventilation [53]. Leptin resistance has been proposed as one mechanism that contributes to OHS.
●Pre-clinical animal studies – Genetically obese leptin-deficient mice demonstrate many of the characteristics of human OHS including impaired respiratory mechanics, depressed ventilatory responsiveness to CO2 and awake hypoventilation [54]. Leptin replacement improved the sensitivity to CO2 and resulted in increased minute ventilation [55].
●A study has shown acute intranasal leptin in diet-induced obese mice reduced oxygen desaturation events in rapid eye movement (REM) sleep and increased ventilation in non-REM and REM sleep. Chronic intranasal leptin decreased food intake and body weight [56].
●Human studies – Elevated serum leptin levels have been reported in patients with obesity, particularly those with OHS [57,58]. In one study obese hypercapnic patients had higher serum leptin levels than eucapnic patients (39 versus 21 ng/ml) and serum leptin predicted the presence of hypercapnia [57]. It was hypothesized that the increased leptin levels may be a compensatory response to leptin resistance and/or an effort to maintain alveolar ventilation in the setting of a high ventilatory load due to obesity and increased upper airway resistance [57]. Another study reported higher leptin levels in patients with OHS compared with eucapnic patients with OSA of the same degree [58].
Studies that examine the impact of noninvasive positive airway pressure therapy on leptin levels are conflicting. One study of OHS patients reported that compared with those who were noncompliant with noninvasive ventilation (NIV), those who were compliant experienced a reduction in leptin levels [59]. In contrast, a trial of 35 patients with OHS reported that compared with lifestyle modifications, NIV did not reduce leptin levels, despite improvements in sleep and daytime gas exchange [60]. Finally, in a study of six patients with OHS (sleep hypoventilation but without OSA) leptin levels increased after treatment with NIV; the increase correlated with the degree of improvement in the ventilatory sensitivity to CO2 [61].
Carbon dioxide overproduction — Excess CO2 production is associated with increased body surface area [62]. This was supported by a study that compared patients with OSA and OHS with patients who had OSA at the same severity [62]. Higher PaCO2, lower PaO2, and greater CO2 production were found in those with OHS without any differences in indices of alveolar ventilation (eg, minute ventilation, dead space). Excess CO2 production is also supported by the observation that weight loss alone decreases PaCO2 during wakefulness in patients with OHS (figure 2) [63]. (See "Mechanisms, causes, and effects of hypercapnia", section on 'Increased production of carbon dioxide'.)
SUMMARY AND RECOMMENDATIONS
●Obesity hypoventilation syndrome (OHS) is defined as the presence of awake alveolar hypoventilation (arterial carbon dioxide tension [PaCO2] >45 mmHg) in an obese individual (body mass index [BMI] ≥30 kg/m2) which cannot be attributed to other conditions associated with alveolar hypoventilation (eg, neuromuscular disorders). (See 'Introduction' above and "Clinical manifestations and diagnosis of obesity hypoventilation syndrome".)
●OHS is uncommon in the general population but is more prevalent in patients with obesity and patients with obstructive sleep apnea (OSA). (See 'Epidemiology' above.)
●Alveolar hypoventilation in patients with obesity occurs when the normal compensatory ventilatory mechanisms that maintain adequate ventilation fail. OHS is likely due to a complex interaction of several physiologic abnormalities, including sleep disordered breathing (obstructive sleep apnea and/or sleep hypoventilation), altered pulmonary mechanics (restriction, ventilation/perfusion mismatching, reduced respiratory muscle strength), altered ventilatory control (reduced neural drive and ventilatory responsiveness, leptin resistance), and increased carbon dioxide production. (See 'Pathogenesis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Suratt, MD, who contributed to an earlier version of this topic review.
