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Department of Medicine, University of Virginia School of Medicine and the University of Virginia Health System, Division of Pulmonary & Critical Care Medicine, Box 800546, Charlottesville, VA 22908-00546
Obesity can profoundly alter pulmonary function and diminish exercise capacity by its adverse effects on respiratory mechanics, resistance within the respiratory system, respiratory muscle function, lung volumes, work and energy cost of breathing, control of breathing, and gas exchange. Weight loss can reverse many of the alterations of pulmonary function produced by obesity. Obesity places the patient at risk of aspiration pneumonia, pulmonary thromboembolism, and respiratory failure. It is the most common precipitating factor for obstructive sleep apnea and is a requirement for the obesity hypoventilation syndrome, both of which are associated with substantial morbidity and increased mortality. There are numerous medical and surgical therapies for obstructive sleep apnea and obesity hypoventilation. Weight reduction in the obese is among the most effective of these measures.
Obesity can have profound adverse effects on the respiratory system. It can cause alterations in respiratory mechanics, respiratory muscle strength and endurance, pulmonary gas exchange, control of breathing, pulmonary function tests, and exercise capacity. Common complaints include dyspnea on exertion and exercise intolerance. Obese persons are at increased risk of developing respiratory complications such as atelectasis, severe hypoxemia, pulmonary embolism, aspiration pneumonia and acute ventilatory failure, particularly in the perioperative and postoperative periods.
A subgroup of obese persons develop chronic daytime hypoventilation, defined as a sustained increase in arterial carbon dioxide tension (Paco2), exceeding 45 mm Hg. Those that do are typically extremely obese. The term obesity-hypoventilation syndrome (OHS) is used to describe this combination of severe obesity and diurnal hypoventilation. Obese persons without OHS are said to have simple or uncomplicated obesity.
Obesity is also the most common predisposing factor to obstructive sleep apnea (OSA) syndrome. If defined as a body mass index (BMI) greater than 28 kg/m2, obesity is present in 60 to 90% of OSA patients evaluated in sleep clinics.
The first portion of this review will outline the effects of simple obesity and OHS on pulmonary function, the clinical implication of these effects as well as the effect of weight loss on the lung function of obese persons. The second portion will discuss the underlying pathophysiology, presenting signs and symptoms. Diagnosis and treatment of OSA and OHS will be discussed. The role and importance of obesity in these conditions will be emphasized. Because failure to appreciate and anticipate the effects of obesity on pulmonary function can result in adverse health consequences, and because OSA syndrome is a major public health problem that is often unsuspected, it is essential that physicians, other healthcare providers, and the public at large become more aware of the effect of obesity on the respiratory system.
reported that in simple or uncomplicated obesity, chest wall and total respiratory system compliance (Table 1) were 92 and 80%, respectively, of predicted normal values. These values were substantially lower in patients with OHS, whose chest wall and total respiratory system compliance were 37 and 44% of normal, respectively.
The presumed mechanism explaining the decreased chest wall compliance associated with obesity has been the simple mechanical effect of adipose tissue pressing on the thoracic cage. However this hypothesis may not be completely accurate. Although excess weight does present an added inspiratory load, it is of the threshold type. Inspiratory threshold load is the load that the respiratory muscles must overcome before inspiratory flow can begin. When chest wall and respiratory system compliance are measured with techniques such as the pulse airflow technique that allow the separation of threshold from other inspiratory loads, chest wall compliance is relatively normal in simple obesity.
noted that lung resistance in OHS is the same as in simple obesity, but chest wall and total respiratory resistances are higher. The primary mechanism for the increased lung and total respiratory system resistance is reduced lung volume. After correcting for reductions in functional residual capacity (FRC), specific airway conductance, which is the inverse of airway resistance, may be near normal or reduced to 50 to 70% of normal.
There are several potential mechanisms for the decreased respiratory muscle strength and endurance in simple obesity and OHS. An overstretched diaphragm, especially in the supine position, would place this respiratory muscle at a mechanical disadvantage, leading to decreased inspiratory muscle strength and efficiency.
The rapidity of this response is most consistent with relief of respiratory muscle fatigue. Respiratory muscle fatigue will occur if the work of breathing (WOB) is excessive and/or respiratory muscles operate inefficiently. Because patients with OHS have both increased work and energy cost of breathing (see below) and impaired respiratory muscle strength, endurance, and efficiency, it is not too surprising to find evidence of respiratory muscle fatigue in these patients.
Spirometry and Lung Volumes
The effect of obesity on spirometry and lung volumes is complicated and influenced by the degree of obesity, age, and type of body fat distribution (central or peripheral) (Figure 1). The most frequent pulmonary function test abnormality associated with obesity is a decreased expiratory reserve volume (ERV). The proposed mechanism of this reduction is displacement of the diaphragm into the chest by the obese abdomen. The FEV1-to-FVC ratio is also consistently increased.
studied 43 healthy, young, nonsmoking obese persons, with an average body weight of 159 kg, BMI of 54 kg/m2, and BW/HT of 0.93 kg/cm. When the BW/HT exceeded 0.7 kg/cm, ERV was approximately 60% of normal; vital capacity (VC), FRC, total lung capacity (TLC), and MVV were normal in most. The decreased ERV in the setting of a normal VC indicates that the inspiratory capacity is greater than in a nonobese person.
The ERV of patients with OHS is similar to that of the most severe cases of simple obesity; the TLC is approximately 20% smaller, the FEV1 and MVV are approximately 40% smaller than in simple obesity, and the FRC is approximately 75 to 80% of predicted.
Thus, except for the ERV, lung volumes are generally well-maintained in otherwise healthy persons with mild to moderate obesity. Only the very obese and those with OHS seem likely to have a reduction in other lung volumes. Some light is shed upon this somewhat surprising result when one focuses on the distribution of fat rather than total body weight. Collins et al
examined 42 healthy, normal weight or mildly obese male firefighters with a median age of 35 years. Compared with subjects of normal weight, mildly obese persons (between 120 and 150% ideal body weight) had similar mean VC, FEV1, and TLC values (percentage predicted). In contrast, the FVC, FEV1, and TLC for patients with a waist-to-hip ratio (WHR)≥0.95 (upper body fat distribution) were significantly lower than for subjects with a WHR<0.95 (lower body fat distribution). Biceps skin fold thickness had the strongest inverse relationship with TLC, FEV1, and FVC compared with other anthropometric measures. Lazarus et al
noted that after adjustment for BMI, the ratio of abdominal girth to hip breadth and subscapular skinfold thickness were negatively associated with both FVC and FEV1. Interestingly, the influence of fat distribution on lung function diminished with age. Because increased WHR and abdominal girth-to-hip breadth ratio directly measure and subscapular and biceps skinfold thickness indirectly measure upper body fat distribution, these studies suggest that upper but not lower body fat significantly effects pulmonary function. These results extend similar findings in morbidly obese subjects where those with greater upper body fat distribution had more severe lung volume compromise.
Unfortunately, neither the Collins study nor the Lazarus study included women or commented on potential ethnic differences.
The most likely explanation for the effect of fat distribution on pulmonary function tests is a mechanical one, whereby additional adipose tissue in the chest wall, abdominal wall, and within the abdomen simply compress the thoracic cage, diaphragm, and lungs. The consequences are a decrease in diaphragm descent, lung compliance, chest wall compliance, and elastic recoil, resulting in decreased lung volumes. Although lower body adipose tissue contributes to the BMI, it is too distant to have an effect on pulmonary function. Thus, although an overall obesity index such as BMI may not correlate well with lung volumes, a fat distribution index may.
Work and Energy Cost of Breathing
The elevated total respiratory resistance and compliance and inspiratory threshold load associated with obesity increase the work and energy cost of breathing.
As Table 3 indicates, simple obesity is associated with a WOB that is 70% higher than normal and an energy or oxygen cost of breathing that is 4 times higher than normal. In contrast, patients with OHS have a WOB that is 280% higher than normal and an energy cost of breathing almost 10 times normal. If OSA or upper airway resistance syndrome are present (below), increased respiratory effort against an occluded upper airway will occur during sleep, further increasing the work and energy cost of breathing. Breathing efficiency is similar in simple obesity and OHS and approximately one half of normal.
Although some studies investigating ventilatory drive in simple obesity and OHS have demonstrated that the ventilatory responses to inhalation of carbon dioxide (DVE/DPco2) are reduced by approximately 40% in simple obesity and by 65% in OHS, others have indicated a normal response to inhaled CO2 in OHS (Table 4).
However, there is an inherent problem with using ventilatory responses as a marker of respiratory drive because minute ventilation response to a stimulus may also be influenced by respiratory muscle function and respiratory system mechanics. To overcome this difficulty, investigators have measured the mouth occlusion pressure (P0.1), the pressure measured during a 0.1-second interruption of airflow. The P0.1 is believed to reflect neurogenic drive to the respiratory muscles. The diaphragmatic electromyogram (EMGdi) response to CO2 is also thought to be an indicator of respiratory muscle drive.
These P0.1 values for OHS are similar to those reported for eucapnic patients with OSA. The EMGdi responses to CO2 for eucapnic patients with OSA and for OHS are similar to each other and to healthy control subjects, but half the value noted in patients with simple obesity.
Thus, the cumulative data indicates that subjects with simple obesity have an enhanced respiratory drive. In contrast, the respiratory drive of subjects with OHS is either depressed or inappropriately normal, considering their elevated PacO2 as well as the augmented ventilatory drive of persons with uncomplicated obesity.
Pattern of Breathing
With eucapnic morbidly obese patients, the respiratory rate (RR) is approximately 40% higher than normal at rest, the tidal volume (Vt) at rest and maximal exercise is normal and the duration of inspiration as a fraction of total breath duration (Ti/Ttot) is normal (Table 4).
Although severely obese persons are often hypoxemic, with a widened alveolar-arteriolar oxygen tension gradient (a-aPo2), the hypoxemia may be mild, present in the supine position only, and even absent (Table 5).
The mechanism of this hypoxemia is mismatch of ventilation and perfusion, resulting in shunt physiology. Although the lung bases are well perfused, they are underventilated secondary to airway closure and alveolar collapse or atelectasis.
However, most of the reduction in PaO2 in OHS is a result of the increase in PaCO2 (see below).
Table 5Gas Exchange in Healthy Subjects, Obese Subjects, and OHS
PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of oxygen in arterial blood; a–aPo2, alveolar–arterial oxygen gradient (difference in partial pressure of oxygen between alveolar gas and arterial blood); Dlco, diffusing capacity for carbon monoxide. Data from ref.
Despite the increase of work and energy cost of breathing, the decrease in breathing efficiency, and the decrease in respiratory muscle strength and endurance (all of which can result in hypoventilation) caused by obesity, the majority of persons with severe obesity are eucapnic.
By definition, patients with OHS have an elevated PaCO2. The cause of this hypoventilation is probably multifactorial (Table 6). Evidence to support the presence of an impaired central drive to breathe, decreased respiratory muscle strength and endurance, respiratory muscle fatigue, and increased work and energy cost of breathing in patients with OHS has already been discussed. However, the extent of elevation in PaCO2 is inversely proportional to the FEV1.
This finding indicates that abnormal respiratory mechanics contribute to the hypercapnia associated with OHS. In addition, patients with OHS return to eucapnia after treatment with either nasal continuous positive airway pressure (CPAP) or tracheostomy without a change in hypercapnic responsiveness. This fact, coupled with the finding that eucapnic persons with OSA have similar P0.1 and EMGdi values, suggests that some abnormality other than or in addition to diminished ventilatory drive is playing a role in the genesis of the hypercapnia.
Ventilatory load compensation, which is the normal response taken to defend alveolar ventilation when mechanical impediments are placed on the respiratory system, is impaired in OSA compared with weight-matched control subjects.
This abnormal response to elastic and resistive loads may play a role in the development of hypercapnia in patients with OSA and OHS as well.
As in patients with OHS, patients with chronic obstructive pulmonary disease (COPD) have an increased energy cost and WOB because of airflow obstruction and increased dead space-to-tidal volume ratio (Vds/Vt).
This increased Vds/Vt is caused by parenchymal lung disease as well as the rapid shallow breathing pattern adopted by patients with COPD. In addition, patients with COPD also have decreased respiratory muscle efficiency because of decreased blood supply to the respiratory muscles and dynamic hyperinflation flattening the diaphragm’s normal dome-shaped configuration.
As mentioned above, this combination of excessive WOB and inefficient ventilatory muscles increases the likelihood of respiratory muscle fatigue. Also, there is some evidence for decreased CO2 responsiveness in patients with COPD.
Consequently, coexistent COPD would be expected to contribute to hypercapnia in obese persons.
Although the majority of persons with OHS have OSA, the exact contribution of obstructive sleep-disordered breathing to the elevated Paco2 is unclear (see below). The single breath diffusing capacity for CO (Dlco) is normal in simple obesity and slightly diminished in OHS.
The effect of body weight on Vo2 is more pronounced on the treadmill because the work rate must be even greater to move the entire body rather than just the legs. In young obese persons, the maximal cycle ergometer work rate (Watts), maximal exercise Vo2 (Vo2max), and maximal exercise minute ventilation are approximately 90% of normal.
Overall, young adults with simple obesity have nearly normal exercise capacity. No exercise data exists for patients with OHS.
Effect of Weight Loss on Lung Function
In simple obesity, the most significant change associated with weight loss is an increase in ERV. For instance, a decrease in BMI from 50 to 37 kg/m2 results in a 75% increase in ERV, a 25% increase in RV and FRC, and a 10% increase in MVV.
Weight loss in simple obesity also results in a small increase in VC, a slight decrease in Dlco, an occasional increase in Pao2, a substantial reduction in CO2 production during exercise, and a small but statistically insignificant decrease in DVE/DPaco2; the FEV1/FVC, TLC, and compliance change little.
In OHS, with an average weight loss of 35 kg, VC increases from 53 to 84% of predicted, ERV increases from 33 to 59% of predicted, FRC increases from 59 to 75% of predicted, Paco2 decreases and Pao2 increases by 15 mm Hg, and MVV increases significantly.
Proposed mechanisms for this enhanced risk include increased intra-abdominal pressure, greater incidence of gastroesophageal reflux, higher volume of gastric fluid, and a lower gastric pH in fasting obese patients.
Mechanical ventilation of obese persons can be difficult. Because of decreased respiratory system compliance and increased resistance, a tidal volume based on the patient’s actual body weight while he or she is on a ventilator will likely result in high airway pressures, alveolar overdistention, and potentially barotrauma, such as pneumothorax. The initial tidal volume should therefore be calculated according to ideal body weight and then adjusted according to airway pressures and arterial blood gases. The use of positive end-expiratory pressure should be used to prevent end-expiratory closure and atelectasis. Positioning the patient in reverse Trendelenburg at 45° may facilitate weaning from mechanical ventilation.
Compared with 0° and 90°, this position results in a larger tidal volume and lower respiratory rate.
Acute postoperative respiratory events, including respiratory failure, are twice as likely to occur in obese patients compared with nonobese patients, with obese blunt trauma patients having a particularly poor outcome.
Postoperative pulmonary dysfunction is accentuated by thoracic and upper abdominal incisions. To minimize the likelihood of postoperative respiratory complications in obese patients, pain control strategies with minimal respiratory depression, such as continuous epidural patient-controlled analgesia, respiratory monitoring with pulse oximetry, aggressive chest physiotherapy, early mobilization, nursing in the semiupright position, and aggressive deep vein thrombosis prophylaxis are recommended.
Obesity and Sleep Disordered Breathing
An apnea is defined as the complete or near complete cessation of airflow that lasts for at least 10 seconds.
They are considered obstructive if there is continued or increasing respiratory effort despite absent or diminished airflow or central if there is absent respiratory effort. An event is labeled mixed if it begins as a central apnea or hypopnea and is terminated by an obstructive event (Figure 3).
Recent investigations have demonstrated that narrowing of the upper airway alone, without an accompanying apnea, hypopnea, or oxyhemoglobin desaturation, can fragment sleep and cause daytime tiredness and/or sleepiness.
This clinical entity has been termed the upper airway resistance syndrome (UARS). At the present time, this condition can be reliably diagnosed only by measuring esophageal pressure. In this syndrome, esophageal pressure becomes more negative with each inspiration, indicating increased respiratory effort, until an arousal from sleep occurs (Figure 2C).
The term hypoventilation is used when oxyhemoglobin desaturation (and elevated arterial carbon dioxide tension if measured) is present, but there are no abnormalities in the pattern of breathing. That is, there is a relatively constant or slowly diminishing oxyhemoglobin desaturation, without the cyclic, episodic, or repetitive changes in oxygen saturation associated with apneas and hypopneas or the arousal that terminates these abnormal breathing events (Fig 4). Because everyone hypoventilates somewhat when they fall asleep, and often with rapid eye movements during rapid eye movement (REM)-sleep, hypoventilation is considered abnormal only if associated with clinically significant oxyhemoglobin desaturation (ie, less than 88 to 90%) or hypercapnia.
Snoring is an inspiratory sound produced by vibration of the soft portions of the oro and nasopharynx. For snoring to occur, you need both the proper structure (ie, a long floppy uvula and soft palate) and exposure to an inspiratory pressure negative enough to set these tissues in motion. The reason more than 80% of persons with OSA snore is because the most common site of upper airway abnormality and narrowing is the region around the soft palate.
Indicators of the severity of sleep-disordered breathing include the apnea index (the number of apneas per hour of sleep), the hypopnea index (the number of hypopneas per hour of sleep), the respiratory disturbance index (RDI; the number of apneas plus hypopneas per hour of sleep), and the oxyhemoglobin desaturation index (the number of oxyhemoglobin desaturation episodes ≥3% per hour).
Patients with the “Pickwickian” syndrome, first described by Burwell in 1956, complain of daytime hypersomnolence and dyspnea, are morbidly obese, plethoric (from polycythemia), and cyanotic (from hypoxemia), have both hypoxemia and hypercapnia on arterial blood gases, and have signs of pulmonary hypertension and right ventricular failure.
The term “Pickwickian” is best reserved for these persons on the severe end of the OHS spectrum.
The multiple sleep latency test (MSLT) is used in the assessment and diagnosis of disorders of excessive sleepiness. A series of 4 or 5 opportunities to sleep is administered to a patient at 2-hour intervals using standard procedures. Sleepiness is measured as the speed of falling asleep (sleep latency); the presence of REM sleep is also noted. A mean sleep latency for all naps of less than 5 minutes is indicative of severe sleepiness; 5 to 8 minutes, moderate sleepiness; 8 to 10 minutes, mild sleepiness; and greater than 10 minutes, normal. The appearance of REM sleep in 2 or more naps is suggestive of narcolepsy.
The pharynx is typically divided into 3 segments: the nasopharynx (end of the nasal septum to the margin of the soft palate), the oropharynx (free margin of the soft palate to the tip of the epiglottis), which is further divided into the retropalatal and retroglossal regions, and the hypopharynx (tip of the epiglottis to the vocal cords) (Figure 5). In one study, 75% of patients had more than 1 site of narrowing, the retropalatal region or velopharynx being the most common site.
Because a decrease in size or narrowing of the human upper airway or pharynx is the underlying cause of OSA, persons with this condition must have some abnormality or abnormalities of the determinants of the caliber of their upper airway. According to the “balance of pressures” concept proposed by Remmers et al and Brouillette and Thach, there are 5 major determinants of the caliber of the upper airway (Figure 6): (1) the baseline pharyngeal area, which is determined by both craniofacial and soft tissue structures (Figure 5); (2) the compliance or collapsibility of the airway; (3) the luminal pressure (PL), which on inspiration is negative because of the upwardly transmitted negative intrapleural pressure and tends to narrow the airway; (4) the pressure acting on the outside surface of the pharyngeal wall (Ptis), which can be positive, and also tends to collapse the airway; examples include compression by the lateral pharyngeal fat pad, a large neck, the effect of gravity on submandibular fat, and a large tongue confined to a small oral cavity; and (5) the pressure exerted by the pharyngeal dilating muscles (Pmusc), which is directed outwards and functions to increase cross-sectional area and decrease pharyngeal compliance.
In addition, there is theoretical evidence that the shape of the upper airway is also important. Compared with the elliptically shaped airways of normal control subjects, the long axis of which is oriented transversely, the pharynx of patients with OSA has more of an anteroposterior or longitudinal alignment. Such an orientation could decrease Pmusc by diminishing the mechanical effectiveness of upper airway muscle contraction.
Finally, lung volume independently influences upper airway caliber, resistance, and compliance. Decreased lung volume results in a decrease in the baseline area of the pharynx, an increase in its compliance or collapsibility, and the loss of caudal traction on the trachea.
Although narrowing of the human upper airway is the primary event in OSA, the occurrence of oxyhemoglobin desaturation during the abnormal respiratory event is dependent on several other factors. The primary determinants of oxyhemoglobin desaturation with hypoventilation, an apnea, or hypopnea include: (1) the length of the abnormal respiratory event (the longer the event, the more likely oxyhemoglobin desaturation will occur) (2) the type of respiratory event, obstructive events being associated with respiratory effort and therefore greater oxygen consumption than central events; (3) the quantity of oxygen stored in the lungs, which is proportional to the lung volume and the fractional concentration of oxygen in the alveoli (a small lung volume is associated with greater desaturation than a large lung volume); (4) the mixed venous oxygen saturation (the lower this saturation, the more rapid the rate of fall in arterial oxyhemoglobin saturation); and (5) the baseline arterial oxygen saturation: the lower the value, the closer you are to the knee of the oxyhemoglobin dissociation curve at the start of the abnormal respiratory event and the more likely you are to desaturate (Figure 7).
The latter exacerbates the decreased lung volume associated with assumption of the supine position. In addition, the effect of gravity on a large neck or parapharyngeal fat may increase Ptis. The overall result is an increase in upper airway resistance caused by the decrease in cross-sectional area and increase in compliance or collapsibility of the upper airway.
Stiffer, smaller lungs and resultant atelectasis may also cause a decrease in baseline oxyhemoglobin saturation and the other determinants of the degree of oxyhemoglobin desaturation with an apnea, hypopnea, or hypoventilation.
The pharynx of persons without OSA has sufficient “reserve” to tolerate this increase in upper airway resistance and collapsibility associated with sleep. In contrast, persons with OSA have some predisposing condition, either a pharynx with a baseline area that is too small, or an abnormality in 1 or more of the determinants of upper airway caliber mentioned above. Thus when they fall asleep, their upper airway cannot tolerate this decrease in Pmusc and lung volume and increase in Ptis. The result is an upper airway resistance of sufficient magnitude to cause physiologic consequences (see below).
Those factors that have been shown to predispose to OSA and how they interact with the determinants of upper airway caliber described above are listed in Figure 5.
Because REM sleep is associated with greater muscle hypotonia compared with non-REM sleep, apneas and hypopneas are more likely to occur.
The result is more frequent and more severe episodes of increased upper airway resistance and oxyhemoglobin desaturation compared with non-REM sleep.
To predispose to OSA, obesity must influence 1 or more of the above mentioned determinants of upper airway caliber or of degree of oxyhemoglobin desaturation associated with a given abnormal respiratory event. As it turns out, there is evidence that obesity can impact all of these determinants, which explains not only why obesity is the most common factor predisposing to OSA, but why obese persons with OSA are more likely to have more severe clinical consequences than their nonobese counterparts (Figure 8).
Although it is unclear whether the predominant mechanism is increased Ptis or simply excessive parapharyngeal tissue without an increase in Ptis, the majority of studies indicate that, compared with weight-matched control subjects, obese patients with OSA have a smaller baseline upper airway cross sectional area. This narrowing is located predominantly in the retropalatal region.
Logic would dictate that excessive adipose tissue should be the cause of this decreased area, and there is evidence to support this hypothesis. Using MRI, which can distinguish soft tissue from fat, one study indicated that compared with weight-matched control subjects, obese patients with OSA had excess fat deposition in the soft palate, tongue, and in areas posterior and lateral to the oropharynx at the level of the palate.
Two other MRI studies confirmed the smaller baseline pharyngeal area in obese subjects with OSA, and also demonstrated the presence of a larger volume of adipose tissue adjacent to the pharyngeal airway.
Moreover, not only did the volume of this parapharyngeal fat correlate with the degree of OSA, but weight loss resulted in a substantial decrease in both pharyngeal adipose tissue volume and the severity of OSA.
confirmed that airway size is smaller in patients with sleep apnea, their findings indicated that it was the thickness of the lateral pharyngeal wall and not the size of the soft palate, tongue, or parapharyngeal fat pads that was the major anatomic factor causing airway narrowing in apneics. Moreover, using a proton spectroscopic technique called hydrogen ultra-thin phase-encoded spectroscopy with MRI, he demonstrated that this increased thickness of the lateral pharyngeal walls was not caused by increased fat infiltration or edema.
He went on to hypothesize that obesity may predispose to sleep apnea by increasing the size of the upper airway soft tissue structures themselves (tongue, soft palate, lateral pharyngeal walls), rather than by the direct deposition of fat in the parapharyngeal fat pads or by compressing the lateral walls by these fat pads. Thus, although most evidence supports a smaller baseline upper airway caliber in obese patients, the exact mechanism of this narrowing remains to be defined.
Fat might also encroach on the upper airway lumen and alter its shape without necessarily reducing its diameter. With MRI, differences in pharyngeal shape but not in cross-sectional area have been documented between obese patients and normal-weight control subjects.
When the pharynx was viewed in coronal section, the airways of healthy, awake control subjects were in the shape of an ellipse, with its long axis oriented transversely. In contrast, awake OSA patients had elliptically shaped airways oriented in an anteroposterior or longitudinal direction. Nonapneic snorers had upper airway shapes intermediate between these 2 groups. Using CT scanning, Schwab et al
Whether the longitudinal orientation of the pharynx in patients with OSA is caused by lateral encroachment by fat (ie, an increase in Ptis) or by pharyngeal dilator muscles pulling the airway anteriorly is unknown. However, as mentioned above, this anteroposterior orientation could diminish the ability of pharyngeal muscles to dilate the upper airway (ie, decreased Pmusc).
Several measures have been used to evaluate the compliance or collapsibility of the human upper airway, including acoustic reflection techniques that measure the lung volume-related change in pharyngeal area, nasopharyngeal resistance, and the critical closing pressure of the airway or Pcrit. Pcrit is the luminal pressure at which the cross-sectional area of the upper airway becomes zero. Regardless of the technique employed, numerous studies have suggested that fat surrounding the human upper airway increases the compliance of the pharynx.
This increased compliance or collapsibility could result from a direct effect on the airway itself or an indirect effect on the function of the upper airway dilator muscles (ie, decreased Pmusc).
As outlined previously, obesity can also result in decreased lung volume. Because pharyngeal area and resistance are directly proportional and compliance inversely proportional to lung volume, obesity can decrease the baseline area and increase the resistance and compliance of the upper airway simply by its effect on lung volume.
Obesity can also impact the degree of oxyhemoglobin desaturation and hypercapnia associated with a given abnormal respiratory event by several mechanisms: (1) increased baseline oxygen consumption and carbon dioxide production and (2) decreased lung volume, which increases mismatch of ventilation and perfusion from airway closure and collapse (atelectasis). The result is decreased oxygen stores in the lung, decreased mixed venous oxygen saturation, and a lower baseline oxyhemoglobin saturation.
Thus, for a given abnormal respiratory event, an obese person is more likely than his nonobese counterpart to have oxyhemoglobin desaturation and hypercapnia.
Neck circumference is a simple clinical measurement that reflects obesity in the region of the upper airway. Studies have indicated that patients with OSA have larger necks than nonapneic snorers and weight-matched control subjects.6148 This parameter is related to obesity, apnea severity, tongue and soft palate size, and maxillary, mandibular, and hyoid bone position; all thought to be important in the pathogenesis of OSA.
These findings suggest the distribution of fat, in particular upper body obesity, rather than total body fat is important to the development of OSA. In one study, only neck circumference and retroglossal space were independent correlates of apnea severity.
Nonetheless, although a more useful predictor of OSA than BMI and other signs and symptoms, neck circumference alone, even if corrected for height, is neither sufficiently sensitive nor specific to avoid the need for further diagnostic testing to establish the diagnosis (r2=0.38; sensitivity, 87%; specificity, 79%; positive predictive value, 66%).
The Relationship between Obesity Hypoventilation Syndrome and Obstructive Sleep Apnea
As mentioned above, the precise underlying pathophysiology of OHS is unclear and probably multifactorial in nature (Table 6). Likewise, although the majority of persons with OHS have OSA, the exact contribution of obstructive sleep-disordered breathing is unclear. Regarding the role of OSA in the pathogenesis of OHS, Sullivan et al
have suggested an explanation for the link between these 2 disorders, a formulation I also espouse. These investigators hypothesize that depressed chemoresponsiveness and ventilatory responses to resistive loads as well as increased arousal thresholds initially serve as a protective adaptation to chronic hypoxia, hypercapnia, and sleep fragmentation. The consequence of this reduced responsiveness is less respiratory effort during inspiration. Studies have demonstrated that the arousal from sleep that opens the upper airway and terminates an apnea or hypopnea is much more tightly linked to the tension time index of the diaphragm than oxyhemoglobin desaturation.
Because the tension-time index of the diaphragm is an indicator of ventilatory effort, the consequence of this diminished inspiratory effort is fewer arousals from sleep. The result is reduced or hypoventilation, rather than no ventilation (ie, an apnea), and episodic hypopneas, apneas, and arousals from sleep are replaced by hypoventilation, with its relatively unwavering hypoxemia and hypercapnia. In addition, this decreased responsiveness, combined with the increased energy expenditure of breathing and the inefficient, sometimes fatigued, muscles of massively obese persons, results in an inability to recover between apneic periods with the normal compensatory hyperventilation response.
This worsens the blood gas abnormalities even further, and a vicious cycle, whereby chronic hypoxemia and hypercarbia further impair chemoresponsiveness, load compensation, and arousal thresholds, ensues.
Interestingly, a common feature of those patients with daytime hypercapnia and OSA is a greater degree of oxyhemoglobin desaturation that occurs during sleep compared with eucapnic OSA patients.
This finding, as well as the improvement in ventilatory responses to both resistive loads and hypercapnia that occurs after treatment of OSA with nasal CPAP, provide supportive evidence for this theory.
Sleep-disordered breathing has 2 primary outcomes: arousal from sleep and oxyhemoglobin desaturation and hypercapnia. The consequences of these abnormalities are depicted in Table 8, Table 9. Although daytime sleepiness, fatigue, irritability, and personality change have been attributed to both nocturnal oxyhemoglobin desaturation and the chronic sleep deprivation caused by sleep fragmentation, arousal from sleep is considered the more important of the 2 factors.
Daytime sleepiness and visual motor incoordination are the presumed cause of the increased rate of automobile (7-fold) and work-related accidents in patients with OSA compared with the general population.
Other associated bradydysrhythmias include marked sinus bradycardia (<30 BPM), sinus arrest (>2.5 seconds), and second-degree atrioventricular block. Supraventricular paroxysmal depolarizations, ventricular paroxysmal depolarizations, atrial fibrillation, atrial flutter, and ventricular tachycardia are also reported. Unless there is coexistent coronary artery disease, increased ventricular paroxysmal de-polarizations and ventricular tachycardia do not typically occur until oxyhemoglobin saturation drops to less than 60 to 65%.
Patients with sleep-disordered breathing may present with all or only a few of the symptoms and signs listed in Table 8, Table 9. Whether a person presents with snoring, symptoms of sleep fragmentation, signs of hypoxemia/hypercarbia, or a combination depends on several factors (Figure 9). As has already been mentioned, everything begins with some predisposing abnormality or abnormalities of the upper airway. When this predisposing factor(s) is combined with the decreased pharyngeal dilator muscle activity and lung volume and increased Ptis that accompanies sleep onset, some degree of upper airway narrowing occurs. If the soft portions of the oro and nasopharynx vibrate, snoring will also result. Depending on the degree of narrowing and resultant increase in upper airway resistance, ventilatory effort may increase to maintain the required ventilation. Because increased ventilatory effort is transmitted to the upper airway in the form of a greater negative intraluminal pressure (PL), the pharynx will become narrower, further increasing upper airway resistance, and a vicious cycle may ensue.
As mentioned above, the arousal from sleep that terminates an apnea or hypopnea is much more tightly linked to increasing ventilatory effort than oxyhemoglobin desaturation. If this “ventilatory effort arousal threshold” is exceeded but the respiratory muscles are still able to compensate for the increased upper airway resistance or load, an arousal from sleep alone, without decreased airflow, that is a hypopnea or apnea, will occur. And without diminished airflow, no oxyhemoglobin desaturation or hypercapnia will result. This condition, which is associated with daytime fatigue, tiredness, and sleepiness due to the sleep fragmentation induced by the arousals, has been termed UARS (see definitions above).
Treatment with sufficient nasal CPAP pressure to eliminate the progressively increasing negative swings in intrapleural pressure and the associated arousals eliminates the daytime symptoms. Interestingly, several patients with UARS, all women, did not even snore.
If ventilatory effort does not exceed its “arousal threshold” before the respiratory muscles becoming unable to compensate for the increased upper airway resistance or load, a decrease in airflow and tidal volume (ie, a hypopnea) results. If airflow ceases completely before arousal from sleep, an apnea occurs.
There are 2 possible outcomes of a hypopnea and apnea: a further increase in ventilatory effort followed by an arousal alone, or hypoxia and hypercapnia, which independently and by further increasing ventilatory effort usually result in an arousal from sleep. The determinants of whether an apnea or hypopnea result in oxyhemoglobin desaturation and hypercapnia, as well as the severity of these abnormalities if they do occur, are discussed above.
Finally, if both the “ventilatory effort arousal threshold” and a person’s ability to compensate for hypoxia, hypercapnia, and respiratory loads are sufficiently blunted, hypoventilation alone, without the periodic arousals that terminate hypopneas, apneas, or increased UAR, results.
Thus, the term OSA is not, strictly speaking, applicable to the entire spectrum of sleep-disordered breathing, but is best reserved for those persons with the most severe form of the disease. The term obstructive sleep-disordered breathing syndrome (OSDB) better describes the entire spectrum of obstructive breathing abnormalities during sleep (Figure 10). On one end of the upper airway resistance continuum there is primary, asymptomatic snoring. This is followed by the UARS, then by the sleep hypopnea syndrome, and finally by the sleep apnea syndrome. The OHS is used to describe persons with OSDB who also have daytime hypoventilation and who are typically morbidly obese. The major factors that determine where along the spectrum of OSDB a patient lies are the “ventilatory effort arousal threshold” and the resistive load compensation. Whether hypoventilation, a hypopnea, or an apnea eventuates in hypoxia and hypercapnia depends on the person’s underlying pulmonary function and the duration of the abnormal respiratory event, the latter determined primarily by the “ventilatory effort arousal threshold.”
Regarding some of the other long-term consequences of OSDB, in several retrospective studies, in which adjustments were made for other risk factors such as weight, age, smoking, and sex, both OSA syndrome and snoring were associated with increased prevalence of hypertension, coronary artery disease, and cerebrovascular accidents,
That snoring alone is associated with increased cardiovascular morbidity suggests that even mild degrees of sleep-disordered breathing may have adverse health effects. Finally, in yet another retrospective study, He et al
demonstrated that untreated significant OSA, defined as an apena index, AI, >20, was associated with excess mortality. Because current morbidity and mortality data is based on retrospective studies, the true impact of sleep-disordered breathing on society remains unknown. A randomized trial is clearly required and is, in fact, presently ongoing.
The mechanism whereby sleep-disordered breathing increases the risk of cardiovascular disease and consequences is unclear. It seems to be mediated by a complex interaction between the mechanical effects of repetitive increased upper airway resistance, the often-associated hypoxia and hypercapnia, and their effect on the autonomic nervous system.
The possibility of sleep-disordered breathing should be considered in any patient with any of the predisposing factors, signs, or symptoms mentioned above (Figure 5 and Table 8, Table 9). Talking with the bed partner, family members, friends or fellow employees can be very helpful, as they will often notice signs such as apneas or falling asleep unintentionally, that the patient may be unaware of or deny. The next step is to estimate a clinical likelihood or pretest probability of sleep-disordered breathing based on a focused history and physical examination. This evaluation should include searching for alternative explanations for symptoms, such as insufficient sleep or shift work causing excessive daytime sleepiness. Those symptoms and signs that have been shown to be most useful in determining the need for further diagnostic evaluation are listed in Table 10. Symptoms of excessive daytime sleepiness, unrefreshing or nonrestorative sleep, morning headaches, cognitive impairment, depression, nocturnal esophageal reflux (due to increases in abdominal pressure during upper airway obstruction), nocturia or enuresis (due to increased intra-abdominal pressure and/or secretion of atrial natriuretic hormone), hearing loss, automatic behavior, sleep drunkenness (disorientation, confusion upon awakening), hypnagogic hallucinations, and night sweats, although commonly reported, do not distinguish sleep apnea from other nonpulmonary sleep disorders.
Table 10Features Most Useful in Determining the Probability of Obstructive Sleep–Disordered Breathing
Nocturnal gasping, choking or resuscitative snorting
BMI >25 kg/m2, or neck circumference ≥17 inches in men, ≥16 inches in women
In any patient presenting with a complaint of daytime sleepiness, the degree sleepiness should be quantified. The sleepier the person, the more likely he has sleep-disordered breathing or some other significant disorder and the more severe the condition, the latter influencing treatment (see below). A reasonable approach is to divide sleepiness into mild, moderate, and severe, based on the frequency of sleep episodes, the degree of impairment of social and occupational function, and in what situations sleep episodes occur.
With mild sleepiness, sleep episodes are infrequent, may not occur every day, and occur at times of rest or when little attention is required, such as while watching TV, reading, or traveling as a passenger. Sleepiness is considered severe when it is present daily and when sleep episodes occur even during activities requiring sustained attention such as eating, conversation, walking, and driving. Moderate sleepiness lies somewhere in between these extremes. Table 11 presents those sleep-inducing situations most commonly reported by patients with OSA syndrome.
Table 11Sleep–Inducing Situations in Sleep Apnea Patients (n=385)
Fatigue may be the only symptom reported. This situation probably results because sleep-disordered breathing develops over a long period, and patients adapt their lifestyles to compensate for it. In addition, sleepiness may be denied because of lack of awareness of risk, embarrassment, or concern regarding punitive actions such as loss of occupation.
Thus the absence of sleepiness can not be used to reliably exclude OSA. In addition, sleep-disordered breathing is not the only cause of EDS, the differential diagnosis of which is listed in Table 12. That is, EDS is not specific for sleep-disordered breathing either.
Table 12Differential Diagnosis of Excessive Daytime Sleepiness
Those physical examination findings that significantly increase the likelihood of sleep-disordered breathing are listed in Table 10. Other features that should be searched for include craniofacial and upper airway abnormalities such as retrognathia; tonsillar hypertrophy, especially in children; and an enlarged soft palate. The size and consistency of the tongue; presence of pharyngeal edema or abnormal reddish coloring of the pharynx; appearance of the soft palate; size, length, and position of the uvula; evidence of trauma; nares, including whether they collapse with inspiration, particularly while the patient is supine, should also be noted (Figure 5).
Unfortunately, subjective impression alone, based on history and physical examination, lacks both sensitivity (52–78%) and specificity (50–79%).
Although plugging clinical variables into regression formulas improves these operating characteristics somewhat (sensitivity, 79–92%; specificity, 50–51%), many involve complicated mathematical formulas that limit their usefulness.
In addition, because the criteria for the diagnosis of OSA in these studies was an RDI >10 to 15, patients with symptoms secondary to UARS would have been missed, decreasing the sensitivity of clinical assessment even further. Whether a post-test probability for OSA of 16 to 21% is low enough will depend on the threshold at which a physician is willing to accept diagnostic uncertainty. The threshold for pursuing further diagnostic testing will probably be lower in patients with severe daytime sleepiness, comorbid illnesses such as coronary artery disease, a driving accident record, and certain occupations (eg, school bus driver).
Recently, a morphometric model that combines measurements of the oral cavity with BMI and neck circumference has been recommended as a screening tool for OSAS.
This model had a sensitivity of 97.6%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 88.5%. Although these results are quite impressive, verification of this morphometric model by other investigators and in other sleep clinic populations must be performed before it can be recommended.
If further diagnostic testing is deemed necessary, options include a formal sleep study or polysomnogram (PSG) and a variety of portable monitoring systems. The criterion standard for diagnosing sleep-disordered breathing is a polysomnogram. Variables typically recorded include electroencephalogram (EEG), electrooculogram, and submental electromyogram (EMG) to stage sleep; airflow and respiratory effort to detect and diagnose hypoventilation or the type of apnea or hypopnea; oxygen saturation; electrocardiogram; and tibialis anterior EMG, to detect periodic leg movements. To decrease the cost of PSG and facilitate treatment, a split-night study can be performed. With a split-night study, the initial portion of the evening is spent determining whether sleep-disordered breathing is present. If sleep-disordered breathing is documented, the remainder of the night is spent finding and titrating the most effective treatment (see below). Using this approach, adequate treatment is rendered 60% of the time and accepted by the patient 62 to 75% of the time.
Because of the cost and frequent unavailability of PSG, investigators have sought less expensive alternatives to formal sleep studies performed in sleep laboratories. These portable recording devices differ in the number and types of parameters measured, varying from pulse oximetry alone to all those variables measured in the sleep laboratory. Each is associated with its own advantages and disadvantages. Advantages of these portable systems include lower cost and greater availability, and tests can be performed in the patient’s home. Of those devices that have been studied and have had the results published in peer-reviewed journals, their sensitivities vary from 78 to 100% and specificity from 67 to 100%, depending on the particular system, the number of variables monitored, and the definition of sleep apnea.
The major disadvantage of portable systems and pulse oximetry is the possibility of false negative results. The likelihood of a false negative study depends on the number of variables monitored and is caused by not staging sleep, observing body position, or detecting UARS. Consequently, a negative result may be a true negative or a false negative caused by the patient’s not falling asleep or sleeping much, not entering REM-sleep, the stage of sleep during which sleep-disordered breathing is most likely to occur, not sleeping in the supine position, the position in which sleep-disordered breathing is most likely to occur, or missing UARS. In addition, these systems cannot diagnose other causes of excessive daytime sleepiness such as periodic limb movement disorder and narcolepsy. Finally, even if these portable systems were 100% specific, a formal PSG is still required if significant sleep-disordered breathing is documented. The optimum nasal CPAP pressure must be determined, and, at least for now, this is done only in a sleep laboratory. However, with the advent of Auto-CPAP devices, some of which have the capability of diagnosing sleep-disordered breathing as well as initiating treatment, this situation may soon change. More studies with larger numbers of patients are required before such strategies can be recommended.
Another approach to the diagnosis of OSA syndrome that has been advocated is the combination of a clinical prediction rule (CPR) based on history and physical examination plus a portable monitoring system. Flemmons and Remmers used a 4-item CPR that included neck circumference, hypertension, habitual snoring, partner reports of frequent choking and gasping during sleep, and the SnoreSat monitor that records snoring and oxyhemoglobin saturation.
employed a 4-channel monitoring system that recorded heart rate, oxyhemoglobin saturation, snoring sounds, and body position (MESAM 4, MAP Medizintechnik, Martinsried, Germany) and a CPR that included BMI ≥29 kg/m2, observed apneas, and involuntary sleep. However, as for the Auto-CPAP devices, more well-designed studies are now needed before such approaches can be recommended as generalizable to a variety of sleep clinic populations. Interestingly, a recent study comparing the cost-utility of treating OSA syndrome based on polysomnography, home testing, and bedside diagnosis concluded that polysomnography was superior.
, the following is the approach I use now to determine the presence of OSDB (Figure 11): (1) Consider the diagnosis of sleep-disordered breathing in anyone with any predisposing factor sign or symptom consistent with the diagnosis (Figure 5, Table 8, Table 9, Table 10); (2) Estimate a clinical likelihood or pretest probability based on the number and predictive value of the patient’s signs and symptoms and predisposing factors, as well as the presence of alternative explanations (eg, insufficient sleep or shift work as the cause of their daytime sleepiness); and (3) Take into account the potential consequences of missing the diagnosis. That is, have a lower threshold for pursuing the diagnosis in a school bus driver, someone who has already had an auto accident, or someone with underlying coronary artery disease.
All persons who complain of excessive daytime sleepiness without another obvious explanation such as insufficient sleep should undergo a split-night PSG. A MSLT should follow if no obvious cause, such as OSA or periodic limb movement disorder, is found on the nocturnal study. Based on Crocker’s data, if the patient is not hypertensive, has a BMI <25 kg/m2, and there are no witnessed apneas, the likelihood of having OSA is very low, and if excessive daytime sleepiness is not present, no further work-up is required.
If the patient is not hypertensive, has no witnessed apneas, but BMI is >25 kg/m2, the probability of significant OSA is low, and nocturnal pulse oximetry should be performed. As per Series study, a positive oximetry study is defined as one with a pattern of repetitive, short duration oxyhemoglobin desaturation.
No absolute (ie, ≤ 90%) or relative (ie, ≥ 3–4%) decrease in oxyhemoglobin saturation is used. With these criteria, the negative predictive value of nocturnal pulse oximetry is quite good (96.9%), but the positive predictive value is not (61.4%). Consequently, every abnormal oximetry requires followup. Finally, for any other constellation of signs or symptoms, perform a split night PSG.
The diagnosis of sleep-disordered breathing, which includes both OHS and OSDB, should also be considered in any person with unexplained daytime hypercapnia, polycythemia, pulmonary hypertension or cor pulmonale. Patients with hypercapnia and pulmonary hypertension secondary to COPD typically have an FeV1 <1 to 1.3 L/min (30% of predicted).
I currently employ the following definitions of OSDB syndrome: AI >20, RDI >30 regardless of symptoms; RDI >5 or number of arousals caused by respiratory effort-related arousal >10, plus some physiologic consequence such as excessive daytime sleepiness, impaired cognition, mood disorder, insomnia, or documented cardiovascular disease such as hypertension, ischemic heart disease, or stroke.
Because patients with OHS may not have discrete hypopneas or apneas, such measures would not be useful in this situation. Consequently, I also monitor the following parameters to help diagnose as well as determine the clinical significance and severity of sleep-disordered breathing: maximum oxyhemoglobin desaturation, presence of cardiac dysrhythmias, and daytime sleepiness, defined either objectively by MSLT or subjectively by a measure such as the Epworth sleepiness scale.
Because optimum therapy for obstructive sleep-disordered breathing depends on the severity of disease, the first task is to estimate this severity. The severity scale I typically employ is given in Table 13.
The goals of treatment are the elimination of all evidence of increased upper airway resistance, which includes hypopneas and apneas, an oxyhemoglobin saturation ≥88 to 90%, no sleep disruption from increased upper airway resistance, hypopneas or apneas, and no snoring. Therapeutic options for sleep-disordered breathing can be divided into conservative, medical, and surgical categories (Table 14).
Table 14Treatment of Obstructive Sleep Disordered Breathing
Although the importance of avoiding factors that can increase the severity of sleep-disordered breathing should be discussed with all patients, if the patient has mild disease and a clear predisposing factor, conservative therapy may be all that is required. Patients should avoid factors that can increase the severity of upper airway resistance such as sleep deprivation, alcohol, sedative-hypnotic agents, and narcotics.
Alcohol, sedative-hypnotic agents, and narcotics increase the frequency of abnormal breathing events during sleep by reducing upper airway muscle tone and prolonging abnormal respiratory events by increasing the arousal threshold.
In some persons, sleep-disordered breathing occurs predominantly in the supine position. Training such persons to not sleep in the supine position may completely alleviate their sleep-disordered breathing, although the longterm effectiveness of this intervention is unclear.
One technique is to place 1 or more tennis balls (or a similar object) in a pocket sewn in the back of a nightshirt or in a sock that is then pinned to the garment. Hopefully in time, the person will be “trained” to sleep in the lateral recumbent position and therefore no longer require the tennis ball(s). Some patients may benefit from elevating the head of the bed at a 30 to 60° angle. The head-up or lateral recumbent position may also benefit the patient who is suboptimally treated on maximally tolerable positive pressure therapy such as CPAP (see below). If present, treatment of increased nasal resistance with a combination of nasal salt solution, nasal steroids, decongestants, and/or antihistamines should be undertaken. Likewise, hypothyroidism and acromegaly should be treated appropriately. Because treatment of hypothyroidism without concomitant treatment of OSA may result in more severe oxyhemoglobin desaturation because of increased oxygen consumption, both should be treated concurrently (ie, with nasal CPAP). Nasal CPAP treatment may be discontinued after treatment of the endocrine abnormality if a follow-up PSG no longer demonstrates significant sleep-disordered breathing.
In obese persons with OSA, dietary weight loss can significantly decrease the number of abnormal respiratory events, oxyhemoglobin desaturation, sleep fragmentation, daytime performance, and cardiovascular and pulmonary function.