Obesity is associated with multiple medical complications. The prevalence of obesity in the United States has doubled since 1980. Currently, 35% of the United States population suffers from obesity. Given its extensive magnitude, it is paramount to address the associated metabolic, cardiovascular, and respiratory complications. Obesity hypoventilation syndrome is one of the major respiratory consequences associated with obesity. The American Academy of Sleep Medicine introduced criteria for the diagnosis of OHS which includes:
The prevalence of OHS in the adult population with BMI >40 kg/m2 ranges between 0.15% to 0.3%. Higher prevalence is seen in the population having obstructive sleep apnea (OSA). Many studies report a prevalence of OHS between 10% to 20% in patients with obesity with OSA. Among hospitalized adults with BMI greater than 35, the reported incidence is around 31%. For unknown reasons, a higher incidence rate is seen in men. Incidence is higher in African American population. OHS is known to occur at a lower BMI range in the Asian community.
Obesity hypoventilation syndrome occurs as a result of complex interactions between multiple pathological processes including diminished respiratory drive, structural and functional respiratory impairment and sleep-related breathing alterations. Chronic steady state hypercapnia establishes as a result of the failure of compensatory ventilatory mechanisms.
Excessive Load on Respiratory System
Respiratory Muscle Weakness
OHS patients have a moderate reduction in their respiratory muscle strength, which typically worsens in the supine position. In morbid obesity, accumulation of fat around the abdominal wall and chest significantly reduces pulmonary volumes and chest wall distensibility. OHS patients have a characteristic pattern of breathing that results in an increase in the airway resistance and a decrease in the distensibility leading to an increased respiratory effort.
Alterations of Respiratory Mechanics
Due to reduced pulmonary distensibility, obese patients suffer reduced ventilation in the lower pulmonary lobes. The alveoli close before the end of the expiration thus producing a characteristic breathing pattern of low tidal volume and an increased respiratory rate, causing an increase in the dead ventilation space. Decreased ventilation of the lower lobes causes alterations in the ventilation-perfusion (V/Q), thus triggering hypoxemia. Total lung capacity (TLC), expiratory reserve volume (ERV) and residual functional capacity (RFC) are reduced in patients with OHS as opposed to eucapnic obese patients.
Blunted Respiratory Drive
Patients with OHS have a blunted respiratory drive in response to a hypercapnic challenge. Multiple possible pathogenic mechanisms have been proposed to explain the blunted respiratory response including possible leptin resistance, genetic predisposition, and sleep-disordered breathing.
Leptin is produced in the adipose tissue. It regulates appetite and stimulates ventilation. Genetically-altered, obese mice with a leptin deficit are phenotypically similar to patients with OHS. These mice develop obesity, suffer from chronic hypercapnia while awake, in spite of increased ventilation which is in response to the increased metabolic production of CO2, and have decreased ventilatory response capacity. Importantly, replacement of leptin reverses chronic hypercapnia thus indicating a possible role in the pathogenesis of OHS.
Intrinsically diminished chemosensitivity to CO2 retention has been reported in OHS patients. It is possible that this familial diminished hypoxic and hypercapnic chemosensitivity could be the underlying reason for hypoventilation in patients with idiopathic obesity hypoventilation syndrome.
Obstructive sleep apnea is seen in about 90% of the patients with OHS. The PaCO2 increases are secondary to the cessation of ventilation during apneic events and continued metabolic production of CO2. Eucapnic patients can normalize the PaCO2 levels via compensatory augmentation of alveolar ventilation which increases CO2 clearance. However, in OHS patients, the compensatory mechanism is disrupted causing retention of CO2. In response to transitory hypercapnia, the renal system decreases bicarbonate clearance to compensate the hypercapnic pH drop. Plasma bicarbonate increases thus causing a gradual bicarbonate build-up. This built up eventually blunts the ventilatory response to carbon dioxide, thus fostering the development of nocturnal hypoventilation.
Almost 5% to 10 % of patients with OHS have sleep hypoventilation and a PaCO2 elevation during sleep of 10 mm Hg or higher. These patients are clinically indistinguishable from those with concomitant OSA. Sustained hypoxia significantly delays the warning signals of decreased ventilation and could potentially contribute to hypoventilation.
While some patients with OHS present with acute on chronic exacerbation of respiratory failure with acute respiratory acidosis, other patients remain clinically stable at the time of diagnosis. Majority patients have classic symptoms including loud snoring, nocturnal choking episodes with witnessed apneas, excessive daytime sleepiness, and morning headaches. Patients often exhibit dyspnea and may have signs of cor pulmonale. Classical physical examination findings include an enlarged neck circumference, crowded oropharynx, a prominent pulmonic component of the second heart sound on cardiac auscultation, and lower extremity edema.
Clinical suspicion should be high in patients with BMI > 30 kg/m2 with unexplained dyspnea on exertion and hypersomnolence . The diagnostic approach's aim is to demonstrate daytime hypoventilation. The most definitive diagnostic test for alveolar hypoventilation is an arterial blood gas analysis. Unfortunately, an ABG is not readily done in an outpatient setting. However, most patients with OHS most common initial presentation is in a hospital setting after presenting with an acute exacerbation where an ABG along with a basic metabolic panel can be done. Their initial laboratory values will show elevated serum bicarbonate level which is typically seen as a result of metabolic compensation of respiratory acidosis which points toward the chronic nature of hypercapnia. This is why a serum bicarbonate level can sometimes serve as a sensitive test to screen for chronic hypercapnia but ultimately an arterial blood gas should show evidence of hypoventilation in complete wakefulness. Polymnography is not required for diagnosis but helps distinguish between patients with coexistent OSA from those with actual sleep hypoventilation. Sleep hypoventilation is defined as a 10 mmHG increase in PaCO2 above that of wakefulness that is not secondary to obstructive apneas or hypopnea. The percent of total sleep time with SpO2 spent below 90% can be a useful polysomnographic variable for evaluation of OHS patients. OHS is a diagnosis of exclusion that requires to be distinguished from disorders that are also associated with hypoventilation. Pulmonary function testing can exclude other causes of hypercapnia such as COPD. In OHS, PFT typically shows a mild to moderate restrictive defect. The expiratory reserve volume is significantly reduced along with mild reductions in maximum expiratory and inspiratory pressures secondary to a combination of altered respiratory mechanics and weak respiratory muscles. Imagings may identify anatomical obstructions such as severe chest-wall disorders. A complete blood count should be obtained to rule out secondary erythrocytosis. Thyroid function tests are to be obtained as well to exclude severe hypothyroidism.
OHS is associated with significantly high rate of morbidity and mortality. Although treatment modalities target different aspects of the underlying pathophysiology, the goal is normalization of arterial carbon dioxide, reduction of oxyhemoglobin desaturation and improvement in symptoms. Several therapeutic options have been tried including positive airway pressure therapy, weight reduction surgery and pharmacotherapy.
Positive Airway Pressure Therapy
Noninvasive positive airway pressure therapy is typically the first-line treatment for OHS. Noninvasive airway pressure therapy significantly reduces the nocturnal built up of PaCO2 and improves sleepiness during the daytime. The available treatment options includes Continuous positive airway pressure (CPAP), bi-level PAP, and other noninvasive ventilation (NIV) modalities. Although there is no defined guidelines for using particular treatment therapy, the current recommendation is to use CPAP if concomitant sleep-related breathing disorders are present. NIMV can be beneficial in patients having hypercapnia in the absence of significant apnea or hypopnea. The German society of pneumology recommends the use of NIMV in the absence of OSA, in the presence of OSA with significant comorbidities and with a CO2 level above 55 mm Hg for over 5 minutes or saturation of under 80% for over 10 minutes. The Canadian thoracic society recommends CPAP use in patients with a minor degree of nocturnal desaturation and no nocturnal rise of PaCO2. Bi-level PAP is the treatment of choice in OHS patients with significant nocturnal desaturation or the nocturnal rise of PaCO2. A recent study compared the 3 standard treatments for OHS including NIV, CPAP, and lifestyle modification. This study showed that both NIV and CPAP significantly improved polysomnographic parameters, although NIV was superior in improving respiratory parameters as compared to other treatment modalities. In a total of 351 patients compared to baseline, at 2 months, the 3 treatments showed a reduction in PaCO2 of 5.5, 3.7, and 3.2 with NIV, CPAP, and lifestyle modification respectively.
Tracheostomy relieves the airway obstruction during sleep, thus improving the alveolar ventilation and waking PaCO2. However, some patients still may not return to eucapnic state post tracheostomy, as it does not affect CO2 production and impaired muscle strength.
Numerous studies have shown improvement in OHS symptoms with weight reduction. Weight loss significantly reduces CO2 production and improve sleep apnea severity and alveolar ventilation. It also improves pulmonary artery hypertension and left ventricular dysfunction which can greatly reduce the cardiovascular compromise in OHS patients. Ideally, lifestyle modification therapy should be tried initially for weight loss. Surgical options should be considered for refractory cases.
Medroxyprogesterone and acetazolamide can potentially reverse the hypercapnia associated with OHS; however, routine use is not recommended given the narrow safety margin and long-term side effects.
Leptin replacement therapy has been shown to relieve nocturnal hypoventilation and airway obstruction during sleep secondary to increased respiratory drive to both upper airway and diaphragm in experimental mice studies, but human use is not recommended.
Limitation to Ventilation
Central Control Defects
Obesity hypoventilation is associated with reduced quality of life and prolonged admission rates and time in intensive care unit. In patients with other medical conditions, such as diabetes, asthma , the mortality rates are significantly high with 23% over 18 months and 46% over 50 months. Early use of CPAP can reduce the associated mortality by 10%.
Obesity is best managed by an interprofessional team including dietitians, nurses, therapists, and pharmacists. Obesity has significant morbidity and mortality if it is left untreated. The key is to educate the patient on the harms of obesity. Patients need to be told to change their lifestyle, become physically active, maintain a healthy weight, and exercise regularly. All current therapies for obesity hypoventilation syndrome are palliative until the patient loses weight.
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