American Journal of Respiratory and Critical Care Medicine

Since the original clarification of the obstructive nature of obstructive sleep apnea (OSA) in 1965, much has been learned about the disorder. It is a condition with a high prevalence with obesity as a major risk factor. It aggregates in families, a relationship that is not simply explained by obesity. Premenopausal women are relatively protected from the disorder because OSA is uncommon in this group. Its prevalence in women rises after menopause. Although OSA is a risk factor for excessive sleepiness, there is developing evidence that it is also a risk factor for hypertension, acute cardiovascular events, and insulin resistance. The first line of therapy is nasal continuous positive airway pressure. Data as to the efficacy of continuous positive airway pressure in severe OSA have come from randomized, placebo-controlled clinical trials with the endpoints being sleepiness, quality of life, and 24-h ambulatory blood pressure. Data are currently less convincing for treatment outcomes in mild to moderate OSA, and new clinical trials to assess outcomes in this group are underway. Thus, even though this field only began toward the end of the first century of the American Thoracic Society, substantial progress has been made, and OSA has increasingly emerged as a major public health concern.

Much of what we have learned about sleep-disordered breathing has occurred in the very recent past. The first description of obstructive sleep apnea (OSA) that recognized that intermittent upper airway obstruction was the major pathogenetic mechanism was in 1965 (1). (For a comprehensive review of the history of development of knowledge about sleep-disordered breathing, see Reference 2.) The development of this area of medicine has been challenging since there was initially considerable skepticism, including a letter to the Lancet that suggested that OSA was a rarity (3). Much of what we have learned about sleep-disordered breathing has occurred in the last 20 years. The progress has been remarkable. It is arguable that the seminal work of Sullivan and colleagues (4), describing nasal continuous positive airway pressure (CPAP) as a therapy, drove development of this area, because CPAP provided a low-risk effective therapy, albeit with adherence issues (5). Also, the realization, based on population-based studies with robust epidemiologic methods, that OSA, far from being rare, was extremely common, as was the association with obesity, was also critical (6), because OSA was then recognized as a major public health issue (7). This article reviews development of new knowledge in several aspects of sleep-disordered breathing but does not cite all relevant articles due to space constraints. It focuses primarily on the most common disorder—that is, OSA—but also briefly discusses other types of sleep-disordered breathing.

That sleep-disordered breathing was not recognized earlier as a major, common clinical disorder is remarkable, as pointed out by Lavie (2). Initial descriptions of sleep-related breathing disorders were made by clinical observation, and first described the pattern of breathing that we now call Cheyne-Stokes' respiration after the physicians who described it (8, 9). (It turns out that it was described earlier by Hunter [see Reference 2]; for current definition of Cheyne-Stokes' respiration, see Reference 10.)

In the late 19th century, there were also clinical descriptions of cases of obesity with extreme excessive sleepiness (see Reference 2). These astute physicians recognized that these cases were similar to the description of the fat boy in the Pickwick Papers (first published in 1835). This led, in time, to use of the term “Pickwickian syndrome” to describe the combination of obesity and marked excessive sleepiness. Recently, however, the term Pickwickian syndrome has come to have a more specific meaning and is restricted to those obese individuals who also have hypoventilation during wakefulness, as described in the classic report of Burwell and colleagues (11).

Physiologic recordings of subjects with Pickwickian features were done in the early 1960s and individuals such as Gerardy and colleagues (12) and Drachman and Gumnit (13) made important contributions. They recognized that with sleep came periodic cessation of respiration associated with marked fluctuations in heart rate. They did not, however, recognize that the reason for the cessation of respiration was obstruction of the upper airway. This was accomplished by more careful assessment of airflow at the nose and mouth, as well as of thoracic movement by Gastaut and coworkers (1).

Thus, obstructive apnea was recognized. The number of investigators of this new disorder at this time was small in number. Investigators from Europe and the United States were brought together at an important conference organized by Lugaresi and colleagues from the Bologna (Italy) group. The conference was entitled “Hypersomnia and Periodic Breathing” and was held in Rimini in 1972 (proceedings are published in the Bulletin de Physiopathologie Respiratoire). This served to further catalyze research in this area. At this time, there was also description of the first definitive treatment—that is, tracheostomy—in two individual case reports (14, 15).

Table 1 gives a historical perspective of key contributions in this area.


1818, 1854

Description by Cheyne (1818) (8) and Stokes (1854) (9) of Cheyne-Stokes' respiration
1956Description of alveolar hypoventilation in obesity (Pickwickian syndrome) (11)
1960, 1962Periodic cessation of respiration recognized in patients with Pickwickian features (12, 13)
1965Recognition that cessation of respiration during sleep was due to airway obstruction (i.e., OSA) (1)
1971, 1974Case reports describing effectiveness of tracheostomy in patients with OSA (14, 15)
1976Case series of pediatric sleep apnea (94)
1978Description of unifying concept re pathogenesis of OSA (40)
1981Description of nasal CPAP (4); description of specific surgery for OSA (90)
1983Identification of CO2-dependent apnea threshold during sleep (102)
1988Hypopneas have same consequences as apneas (17)
1992Identification of neuromuscular compensation (39); intermittent cylic hypoxia leads to hypertension (47)
1993Study with robust epidemiologic methods reveals high prevalence of OSA (6)
1995Family aggregation shown: Cleveland Family Study (30), in Israel (32), and in relatively nonobese Scots (31)
1997Induced obstructive apneas in dogs leads to hypertension (71)
1998Schoolchildren with poor academic performance have high prevalence of OSA. School performance improves after surgical treatment of OSA (97)
1999Introduction of sham CPAP in clinical trials. Efficacy in severe sleep apnea syndrome identified (107)
Improvement with nasal CPAP in blood pressure demonstrated in randomized, placebo-controlled trial (67)

Definition of abbreviations: CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea.

Over the 1990s, a number of studies with robust designs from an epidemiologic standpoint examined the prevalence of sleep-disordered breathing. These studies built on earlier studies of prevalence, one of which showed how a two-stage sampling strategy could be used to more accurately estimate prevalence (16). Hypopneas (decrements in breathing) were also shown to have the same clinical consequences as apnea (17). Disease severity was assessed by the apnea–hypopnea index (AHI; i.e., number of apneas plus hypopneas per hour of sleep). The largest studies in middle-aged adults were done in state employees in Wisconsin (the Wisconsin Sleep Cohort) (6); in the town of Busselton, Australia (18); and in Dauphin and Lebanon counties in Pennsylvania (19, 20). The studies give similar estimates of prevalence of the disorder at different degrees of severity (see Table 2 for data on males; see Table 3 for data on females). Prevalence increases with age in some studies (6, 19), but not all (18), and epidemiologic studies targeted to the elderly show even higher prevalence rates to those given in Tables 2 and 3 (21). Prevalence is higher in men than women but the male-to-female ratio is only of the order of 2–3:1 (compare Tables 2 and 3). Prevalence is particularly low in premenopausal women and increases after menopause (see Table 3) (20).


Name/Citation of Study

Prevalence of AHI ⩾ 5/h (%)

Prevalence of AHI ⩾ 15/h or 20/h (%)

Prevalence of AHI > 5/h and Symptoms of Sleepiness (%)
Young and colleagues (6) (n = 602; 353 M) studied in lab24.09.1*4.0
Bearpark and colleagues (18) (n = 486; all M); 294 studied in lab25.93.43.1
Bixler and colleagues (19) 4,364 (all M); 741 studied in lab

Definition of abbreviations: AHI = apnea–hypopnea index; M = men.

*AHI ⩾ 15 episodes/h (reported by Young and colleagues [6]).

AHI ⩾ 20 episodes/h (reported by Bearpark and colleagues [18] and Bixler and colleagues [19]).



Prevalence of AHI > 15 episodes/h (%)

Sleep Apnea Syndrome*(%)
Young and coworkers (6) (n = 602, 249 females)4.02.0
Bixler and coworkers (20) (12,219 females, 1,000 studied in lab)
 All women2.21.2
 Postmenopausal (overall)3.91.9
 On HRT1.10.5
 Not on HRT

Definition of abbreviations: AHI = apnea–hypopnea index; HRT = hormone replacement therapy.

*In Young and coworkers, defined as AHI > 5 with sleepiness. In Bixler and coworkers, defined as AHI > 10 with reason to treat (e.g., sleepiness and/or hypertension).

These data are for subjects with different degrees of sleep-disordered breathing (i.e., without considering whether they have complaints of excessive sleepiness). When the latter is added as part of the definition (i.e., the OSA syndrome; for definition, see Reference 10), the prevalence numbers drop dramatically (see Tables 2 and 3). Thus, sleepiness is not an inevitable consequence of OSA. By consensus (10), the following terms are used: mild sleep apnea, AHI > 5 and ⩽ 15 episodes/hour; moderate sleep apnea, AHI > 15 and ⩽ 30 episodes/hour; and severe sleep apnea, AHI > 30 episodes/hour. These terms are used throughout this article.


There are a number of risk factors for obstructive sleep apnea (see Table 4) (for review, see Reference 22). In the middle-aged adult population, the most important risk factor is obesity, and even moderate increases in weight increase the risk of OSA (6). Obesity increases the rate of progression of disease, and weight gain further accelerates disease progression (23). In the elderly, however, OSA is not as closely associated with obesity (24). In children, the major risk factor for OSA is adenoidal-tonsillar hypertrophy (25). OSA is common in patients with craniofacial disorders; however, even in individuals without a specific disorder, alterations in craniofacial structure confer risk for OSA. This is particularly significant in patients of Asian descent (26).


Specific craniofacial disorders (e.g., Treacher-Collins, Pierre-Robin syndromes)
Retroposed mandible/maxillae
Adenotonsillar hypertrophy
Nasal problems: septal deviation, allergic rhinitis
Endocrine abnormalities: hypothyroidism/acromegaly
Polycystic ovarian syndrome
Down syndrome
Family aggregation
APOε4 allele (in subjects < 65 yr)

For risk factors, see also Reference 22.

Women who are premenopausal are relatively protected from OSA even in the presence of other risk factors (Table 4). There is, however, a higher prevalence of sleep apnea in women with the polycystic ovarian syndrome (27). Cross-sectional prevalence studies show a fourfold higher prevalence of at least moderate OSA in postmenopausal women as compared with premenopausal women (see Table 3) (20), an effect that is not simply explained by age (28). In postmenopausal women taking hormone replacement therapy, the prevalence of OSA is similar to premenopausal women (see Table 3) (20), although given the increased risk of cardiovascular (CV) disease and uterine and breast cancer with hormone replacement therapy (29), this is currently not a viable therapy for postmenopausal women with OSA. Nevertheless, understanding why premenopausal women are protected from OSA is likely to be a fruitful area of inquiry.


As in many common conditions, genetics also play a role. Family aggregation of OSA has been shown in several populations: an outbred population in Cleveland, Ohio (30); in Scotland (31); in Israel (32); it was also demonstrated using the unique genealogy approach in the founder population of Iceland (33). In these studies, having a first degree relative with OSA increases the relative risk of OSA by the order of 1.5–2.0.

Because obesity is a risk factor for OSA, and itself aggregates in families (for review, see Reference 34), it is reasonable to ask whether familial aggregation of OSA is simply related to the genetics of obesity. Family aggregation is found, however, even after controlling for body mass index (BMI) as a covariate (30), and also when the probands selected for study were relatively nonobese patients with OSA (i.e., BMI < 30 kg/m2) (31).

Although familial aggregation has been shown, little is currently known about the genes conferring risk. The genetic association studies that have been conducted have had apolipoprotein E (APOE) as their major focus. APOε4 is particularly associated with OSA in younger subjects (35). The increased risk in individuals with this allele who are younger than 65 years of having an AHI of more than 15 episodes/hour is 3.1, whereas there is no increase in risk in subjects 65 years and older (35).


There are certain aspects about the pathogenesis that are known. Patients with OSA have narrowed upper airways even during wakefulness as revealed by many imaging studies using multiple imaging modalities (for review of imaging studies, see Reference 36). This is true for both adults and children with OSA, with the airway in the latter being narrowest in the region of overlap between tonsils and adenoids (37). The airway in patients with OSA is not only smaller but is also more collapsible (38).

Despite these abnormalities, during wakefulness the upper airway is patent. Subjects with OSA protect themselves while awake by increased activation of their airway dilator muscles, at least the genioglossus (39). Thus, in the balance of forces model (40)—that is, negative intraluminal pressure promoting collapse of the airway with activation of airway dilator muscles promoting patency—the net effect during wakefulness is for patency.

During sleep, there is reduction of activity of upper airway dilator muscles, thereby shifting the balance of forces toward collapse. Neural control of upper airway motoneurons is complex, involving many different neurotransmitters, several of which are affected by sleep. One important neurotransmitter is likely to be serotonin (5-HT); during sleep there is reduced firing of serotonin raphe cells in the brainstem (for review of evidence, see Reference 41). Serotonin is an excitatory neurotransmitter to upper airway motoneurons. This excitatory effect is largely mediated by serotonin subtype 2A (5-HT2A) receptors (42). Unfortunately, these receptors do not represent an appealing target for pharmaceutical intervention, since agonists of 5-HT2A produce undesired effects due to activation of other neuronal pathways.

Sleep apnea is a progressive disorder, although it progresses at a slow rate (23). There are changes in the upper airway that are likely secondary to the vibration produced by snoring and/or the large swings in intraluminal pressure during sleep. There is evidence of denervation of palatal muscle in subjects with OSA (43, 44) and inflammatory cells infiltrate both the mucosal and muscle layers of the soft palate (44). This has led to the concept of OSA being the progressive snorer's disorder (43). If this concept is correct, then the disorder should be recognized earlier, with intervention occurring at an earlier age (i.e., a prevention strategy).

OSA produces its consequences by a number of mechanisms. There is sleep fragmentation with arousals occurring at the end of the apnea–hypopnea episodes. This fragmentation plays a major role in the excessive sleepiness that occurs in patients with OSA (for review, see Reference 45). There are oscillations of sympathetic output with apnea–hypopnea events (46), and the respiratory disturbances in this disorder produce a unique pattern of repetitive deoxygenation followed by reoxygenation. This is like repetitive episodes of ischemia/reperfusion and results in free radical production and oxidative change. Fletcher and colleagues (47), in seminal studies, developed technology to produce repetitive cycles of deoxygenation/reoxygenation in rodents over weeks. Studies using this strategy have identified damage to hippocampal neurons (48) and to neurons promoting wakefulness (49). The former will likely contribute to the learning problems found in OSA, whereas the latter may be the basis of the residual sleepiness that is found even in well-treated patients with OSA.


Tools have been developed to assess likelihood of apnea. These include questionnaires about symptoms (50) and the multivariable apnea prediction that combines frequency of relevant symptoms with age, sex, and BMI (51). The latter tool has been used as part of a two-stage screening strategy (52). It would seem in the future that screening for OSA in relevant high-risk populations, such as commercial drivers, will become routine.

Definitive diagnosis of OSA still depends on in-laboratory polysomnography. This involves recording of multiple variables during sleep, including the electroencephalogram. Newer technologies are available that allow studies of sleep in the home, in particular all of the relevant respiratory variables. But currently, evidence to support use of these for diagnosis in routine clinical practice is lacking (53). This is likely not because of inadequacy of the technology per se but rather the quality of studies to assess the effectiveness of these alternative strategies. Despite lack of definitive evidence, these ambulatory studies are used frequently to diagnose OSA around the globe, particularly outside the United States (54). There is a rapidly growing demand for diagnosis and treatment of OSA, as it gets increasingly recognized, and infrastructure for diagnosis of treatment is lacking in many countries (54).


OSA is a risk factor for excessive sleepiness. Thus, many patients who seek help clinically complain of falling asleep inappropriately during the day. This results in declines in quality of life, as revealed by general instruments such as the Short Form-36 (55). Three disease-specific quality-of-life instruments have also been developed; they show impairments in patients with sleep apnea syndrome and are now used widely in clinical trials. Sleepiness in OSA leads to excessive pressure for sleep (i.e., short sleep latency), as well as performance decrements, such as frequent lapses due to sleep intruding into wakefulness for brief periods (for review, see Reference 45). Wakefulness in OSA is much less stable (45). These performance decrements put subjects with OSA at increased risk for crashes while driving, as shown originally by George and colleagues (56). A recent meta-analysis puts the average odds ratio for subjects with sleep apnea syndrome for having a crash at 2.5 (57). The latter raises interesting questions for practitioners in deciding about driving privileges.


There are a number of metabolic and endocrine consequences of OSA, with insulin resistance being particularly important. Sleep-disordered breathing is an independent risk factor for insulin resistance. This has been shown in three relatively large studies: (1) a sleep center population in Hong Kong (58); (2) a community-based sample in the Baltimore area (59); and (3) most recently, in a large sample from the Sleep Heart Health Study (60). The increased risk of insulin resistance with sleep-disordered breathing is found after controlling for BMI and, where data were available, for visceral obesity as assessed by waist-to-hip ratio.

Intervention data are, however, quite limited. In the largest study to date (61), improvements in insulin sensitivity were found when OSA was treated with CPAP, although the improvements were largely limited to relatively nonobese subjects. There are also some data, albeit in a small sample, of improvement in glucose control in obese patients with type 2 diabetes who had OSA and were treated with CPAP (62). These studies support the notion that OSA is an integral component of the metabolic syndrome, together with visceral obesity, hypertension, hyperlipidemia, and insulin resistance. The data call for randomized trials assessing efficacy of CPAP therapy on glucose control in obese patients with type 2 diabetes.


One of the most exciting current areas of inquiry is the role of OSA as an independent risk factor for CV disease. This has been a challenging area since obesity is a risk factor for OSA and also for CV disease. Thus, it has been essential to show that the CV risk from OSA is not simply the result of confounding by obesity. This has been done using sufficiently large samples in cohort studies to allow for control for obesity (BMI and/or measures of visceral obesity) as a covariate or by appropriate selection of obese controls in case-control studies. Interestingly, the converse has not occurred and, to date, obesity researchers have largely ignored the possibility that results attributed to obesity might be due to OSA. It is conceivable that OSA is an important part of the mechanism by which obesity leads to CV disease. If so, this is of fundamental significance since it would open an alternative strategy to address the growing epidemic of CV disease related to obesity. Thus, this is a question with major public health significance that needs to be vigorously pursued.

OSA as a Risk Factor for Hypertension

Data for the CV risk of OSA are most convincing for hypertension. Early studies showed that OSA was more prevalent in patients with hypertension and that hypertension was more common in OSA. This association between presence of hypertension and degree of sleep-disordered breathing was then confirmed in large cross-sectional studies (63, 64). Likewise, an association with incident hypertension has been demonstrated in follow-up studies of untreated subjects with sleep-disordered breathing in the Wisconsin Sleep Cohort Study (65). In these studies, the association is found even at low levels of sleep-disordered breathing (i.e., AHI between 5 and 15 episodes/hour), and is present after controlling for BMI as a covariate.

For hypertension, however, current evidence is not only an association but there are also data showing improvements in blood pressure in randomized trials with CPAP (6668), with the placebo being one of the following: an oral medication that subjects are told might improve sleep apnea (66), use of sham CPAP (i.e., CPAP at an ineffective pressure of 0.5–1.0 cm H2O) (67), or CPAP at its lowest setting on conventional machines (i.e., 4.0 cm H2O) (68). There is substantial variation in the reduction of blood pressure in these trials in patients with severe sleep apnea syndrome (see Table 5). Although there was a difference in the degree of sleep-disordered breathing in these studies, probably more important is the percentage of subjects included who had known hypertension (see Table 5). The study with the least effect on blood pressure had, by design, no subjects with known hypertension (66). (This was to avoid the issue of medication use affecting results.) In contrast, the study with the highest percentage of subjects with known hypertension had the largest fall in mean blood pressure (see Table 5) (68). This suggests that those who will benefit from treatment of OSA with respect to reduction in blood pressure are subjects who are hypertensive, a conclusion supported by a secondary analysis of the data collected by Pepperell and colleagues (67). Thus, sleep apnea seems to confer resistance to antihypertensive medications, a conclusion compatible with the observed high prevalence of OSA in subjects with refractory hypertension (69) and the marked reductions in blood pressure when such patients are treated with CPAP (69).



Change in Mean BP (mm Hg) Across 24 h

AHI Episodes/h

Taking Antihypertensive Medications (%)
Faccenda and colleagues (66) (cross-over study)−1.0 (NS)35 (median)0.0
Pepperell and colleagues (67) (parallel group study)−2.5 (p = 0.0013)35.9–38.0 (mean in two groups)18.6
Becker and colleagues (68) (parallel group study)
−9.9 (p = 0.01)
62.5–65.0 (mean in two groups)

Definition of abbreviations: AHI = apnea–hypopnea index; BP = blood pressure.

There is, however, an apparent discrepancy between results of association studies and intervention studies. Specifically, association studies show a relationship to hypertension with even mild to moderate sleep apnea (6365). However, secondary analysis of intervention data (67) shows effects in only the most severe cases. Moreover, studies specifically targeting mild to moderate apnea in randomized trials show no improvements in blood pressure (70). Further trials of CPAP use are needed in patients with mild to moderate sleep apnea who have hypertension to address benefit in this group.

Evidence for the role of OSA as being causative for hypertension also comes from animal studies. Administration of chronic intermittent hypoxia to rats for 8 hours/day simulating the pattern found in OSA increases mean arterial blood pressure by 13.7 mm Hg after 35 days (47). Moreover, inducing OSA in dogs by an ingenious methodology that involves an electronically controlled valve intermittently occluding their trachea results in elevation of systemic blood pressure, which returns to normal when obstructive apneas are no longer produced (71).

OSA and Atherogenesis, CV Events, and Mortality

The level of evidence for the role of OSA in causing other types of CV disease is suggestive but not as complete as for hypertension.

There is evidence of an association from the Sleep Heart Health Study for stroke and myocardial infarctions (72). Case-control studies also show that OSA is a risk factor for myocardial infarction/unstable angina even when control subjects have similar levels of obesity (73). Untreated patients with severe sleep apnea have an increased risk of CV events over a 10-year period when compared with control subjects with similar degrees of obesity (see Figure 1) (74). Treatment with CPAP in severe OSA reduces the risk to the control level (see Figure 1). In mild to moderate disease, the risk is elevated, but not significantly (see Figure 1). This may be an issue of statistical power. Although suggestive that untreated, severe OSA leads to elevated CV events, one cannot rule out the possibility that patients with severe OSA who did not use CPAP were different in other ways and were, for example, also noncompliant with medications to reduce CV risk.

This increased risk of CV events in untreated OSA suggests that OSA might lead to mortality. That OSA can result in fatal outcomes was indicated initially by retrospective studies both in North America and Israel. This has now been shown in the prospective cohort study just described, because patients with severe, untreated OSA had a significant increase in CV deaths (74). When such patients were treated with CPAP, there was no increase in mortality (74).

There is, moreover, a plausible biology whereby sleep apnea could directly contribute to atherogenesis. As discussed earlier, the cyclic deoxygenation/reoxygenation that occurs in OSA leads to free radical production. Thus, OSA is increasingly seen as an oxidative stress disorder (75). The mechanisms involved are summarized in Figure 2 (modified from Reference 75). Changes in many of these steps in OSA have been demonstrated, albeit in small studies. One of the particular advantages of studying OSA is that there is a highly effective treatment (i.e., nasal CPAP), and one can therefore determine whether when OSA is effectively treated there is alteration in these processes, including relevant biomarkers. Studies have shown the following changes with CPAP: reduction in free radical production from white cells (76); reduction in circulating adhesion molecules, specifically intercellular adhesion molecule (77); reduction in high-sensitivity C-reactive protein and interleukin 6 (78); and improvement in endothelial function (79).

Although all of this is highly suggestive for a role of OSA in atherogenesis, we lack, as pointed out by Stradling (80), the definitive proof (i.e., showing reduction in CV events in large-scale randomized trials of treatment of OSA). This is an important question that we need to address.

Although treatment of sleep apnea before nasal CPAP being available was by tracheostomy (14, 15), CPAP quickly became the treatment of choice and remains the mainstay of treatment. Definitive evidence for its efficacy is recent, coming in the last few years. Studies to address efficacy in randomized placebo-controlled trials were stimulated by the provocative article of Wright and colleagues in the British Medical Journal (81), who argued that there is a paucity of robust evidence for the effectiveness of CPAP therapy. The article of Wright and colleagues did lead to a very positive outcome as it stimulated new approaches and studies.

Using the placebo-controlled strategies described above, randomized trials have shown benefit in severe sleep apnea syndrome (i.e., with sleepiness) in many outcomes: for example, subjective sleepiness, objective tests of sleepiness, quality of life, driving performance, and depression scores (for meta-analysis, see Reference 82). Hypertension is also improved (see above). But no benefits of therapy are found in severe sleep apnea if subjects are not sleepy (83). Studies to date have all, however, used short-term outcomes, typically 1 month. A large multicenter National Institutes of Health (NIH)–funded study is currently underway to look at outcomes after 6 months of therapy.

Although the data for severe sleep apnea with sleepiness are convincing, as even Wright and Sheldon now acknowledge (84), data for mild to moderate sleep apnea are less so. The results of these studies are summarized in Table 6 (70, 8588). The only outcome that changes in all studies in which it was assessed is nighttime symptoms (e.g., snoring). Some studies show no change in subjective sleepiness and none in objective measures of sleepiness. With mild to moderate disease, many subjects are not excessively sleepy. Thus, inclusion of such subjects in the studies summarized in Table 6 will reduce the effect of therapy when excessive sleepiness is used as an outcome. Currently, another NIH-funded multicenter study—is assessing efficacy of therapy in mild to moderate sleep apnea in patients who are excessively sleepy before therapy. Given the very high prevalence of mild to moderate OSA in the general population (see Tables 2 and 3), determining who with this level of the disorder will benefit from therapy is a key question.



Subjective Sleepiness

Functional Outcomes

OSA Symptoms

Objective Sleepiness
Redline and colleagues, 1998 (85)++N/A
Engleman and colleagues, 1997 (86)+
Engleman and colleagues, 1999 (87)+++
Monasterio and colleagues, 2001 (88)+
Barnes and colleagues, 2002 (70)*


Definition of abbreviations: N/A = not assessed; OSA = obstructive sleep apnea.

No trial in mild to moderate sleep apnea has used sham continuous positive airway pressure (CPAP). Two studies (85, 88) are parallel group comparison to weight loss, etc., and three are studies with a cross-over design with use of an oral tablet as a placebo (70, 86, 87). + = greater improvement with CPAP; − = no difference between CPAP and control groups.

*No effect on blood pressure in Barnes and coworkers (70).

Functional outcomes refers to general quality-of-life instruments (either Short Form-36 or Nottingham Health Profile).

Although evidence for CPAP use is developing, so too is that for an alternative therapy (i.e., use of intraoral devices that reposition the mandible forward during sleep). Randomized trials using a crossover design with a “placebo” (i.e., wearing a device that does not reposition the mandible) have shown efficacy (89). The reduction in AHI is, however, not as great as with CPAP. Moreover, although CPAP is efficacious in everybody, the intraoral device is not. There are subjects whose AHI does not improve with use of the intraoral device. The reasons for this are unclear, but do necessitate careful follow-up assessment with sleep studies. Thus, the intraoral device is a second-line therapy.

Surgical treatments are also used. One of the main surgical therapies, uvulopalatopharyngoplasty (UPPP), was described in the same year as CPAP (90). Its efficacy has never been assessed in rigorous trials. Rather, there are multiple publications of case series. These series were summarized in an article in 1996 (91) that gave quite a negative view of the outcomes of this surgery. Since then, new surgical approaches to perform UPPP in a less invasive fashion have evolved, as have a number of other surgical approaches (for review, see Reference 92). Unfortunately, however, the studies still tend to be case series and progress in this area has been limited. It seems that surgery does have a role and this role needs to be defined by more robust studies. One view is that surgery has two potential roles: first as an adjunct to nasal CPAP in individuals with nasal obstruction, and second, in patients who fail CPAP due to inability to use the therapy. In this group, surgery is to improve the degree of sleep-disordered breathing but not to cure it (93). It is hoped that we will see development of randomized trials in this area in the future.

The initial description of pediatric sleep apnea was based on a small case series (94). Sleep-disordered breathing is common in children, although, to date, we do not have the population-based epidemiologic studies with complete technology to assess breathing disturbances in sleep to provide accurate estimates of prevalence. Such studies are in progress. Although, as pointed our earlier, adenotonsillar hypertrophy is the major risk factor (25), other aspects of the pathogenesis are similar—for example, smaller airway awake (37) and more collapsible airway (95). What is different is that children do not commonly show the frank arousals in the electroencephalogram at the end of respiratory events that are found in adult subjects (96). Children may have clinical sequelae even in the absence of many respiratory events. Children can have persistent upper airway obstruction leading to sustained hypercapnia and hypoxia. This has been called “obstructive hypoventilation.” This means that criteria for abnormality based on a sleep study are different in children than adults (25). Sleep apnea can have unique consequences in children, such as failure to thrive and learning difficulties (97). A seminal study showed that children in the first grade in the lowest 10th percentile of academic scores had a high prevalence of sleep apnea, and, in those treated with adenotonsillectomy, scores improved after surgery (97). In general, however, there have been limited studies of outcomes of surgical therapy for childhood OSA despite the large number of children having the therapy.

Although this article has primarily focused on the common condition—OSA—there are other forms of sleep-disordered breathing. First, in some patients, there is alveolar hypoventilation that occurs during wakefulness (i.e., the Pickwickian syndrome) (11). This obesity–hypoventilation syndrome can occur in the absence of chronic obstructive pulmonary disease (98). Such patients will typically also have obstructive apneas during sleep but obesity–hypoventilation can occur even in the absence of obvious OSA (99). Obesity–hypoventilation can be effectively treated by nasal intermittent positive pressure ventilation (98). It is currently a condition less well studied than OSA; a recent study indicates that it is common in obese subjects and often unrecognized (100).

Central apnea, where there is episodic loss of neural output to the diaphragm and other respiratory pump muscles, can also occur but is much less common than OSA. It occurs in the periodic breathing at high altitude primarily related to unstable operation of the respiratory control system with hypoxic ventilatory stimulation. There is also an uncommon idiopathic version (101). Subjects with this have high sensitivity to CO2 and low arterial Pco2 awake (typically around 35.0 mm Hg) (101). Thus, they are much closer to the CO2-dependent apnea threshold that is found during sleep (102). Hypocapnia is a risk factor for central sleep apnea. The most common form of central apnea that is found clinically is that described by Cheyne-Stokes' respiration (8, 9). This is found both in patients with stroke (103) and with congestive heart failure (for review, see Reference 104). Initial data, albeit in a small study, indicated that treatment of Cheyne-Stokes' respiration with nasal CPAP in patients with systolic dysfunction improved cardiac outcomes (105). This led to a large randomized multicenter treatment trial conducted in Canada that showed, however, no benefit from CPAP in patients with congestive failure and Cheyne-Stokes' respiration on the endpoints of death or time to heart transplantation (106). This negative result might be related to the change that has occurred recently in medical management of patients with congestive heart failure, in particular the widespread use of β-blockers based on recently reported randomized trials. β-Blockers can affect ventilatory response to hypoxia and hence might directly affect the pathogenesis of Cheyne-Stokes' respiration, as well as its consequences because such patients have increased sympathetic activity (104). Given these changes in medical management of heart failure, there is a need to reassess the prevalence and consequences of Cheyne-Stokes' respiration in such patients.

This area of research is obviously a vibrant one. Much has been learned about sleep apnea, sleep, and other sleep disorders, all in the very recent past. There have been major new discoveries and growing sophistication in the nature of clinical research studies and the level of evidence. There remain, however, major unanswered questions that we are well positioned to answer: for example, (1) what are the functions of sleep both for brain and other organs, (2) does sleep apnea play an important role in the CV consequences of obesity, (3) who with sleep apnea benefits from therapy, and (4) can we develop a new pharmacologic approach to therapy? With the recognition that sleep medicine is a unique discipline, and the enormous impact of sleep disturbance on many aspects of our life, one can anticipate that the rate of progress in gaining new knowledge will further accelerate as we move into the next century of the American Thoracic Society.

The author thanks Mr. Daniel Barrett for his great assistance in preparing this article.

1. Gastaut H, Tassinari CA, Duron B. Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwickian syndrome. Brain Res 1965;2:167–186.
2. Lavie P. Restless nights: understanding snoring and sleep apnea. New Haven, CT: Yale University Press; 2003.
3. Shapiro CM, Catterall JR, Oswald I, Flenley DC. Where are the British sleep apnoea patients? Lancet 1981;2:523.
4. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862–865.
5. Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, Redline S, Henry JN, Getsy JE, Dinges DF. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887–895.
6. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–1235.
7. Phillipson EA. Sleep apnea: a major public health problem. N Engl J Med 1993;328:1271–1273.
8. Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin Hosp Rep 1818;2:216–223.
9. Stokes W. The diseases of the heart and aorta. Dublin, Ireland: Hodges & Smith; 1854.
10. American Academy of Sleep Medicine. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667–689.
11. Burwell CS, Robin ED, Whaley RD, Bickelmann AG. Extreme obesity associated with alveolar hypoventilation: a pickwickian syndrome. Am J Med 1956;21:811–818.
12. Gerardy W, Herberg D, Kuhn HM. Vergleichende untersuchungen der lungenfunktion und des elektroencephalogramms bie zwei patienten mit pickwickian-syndrom [in German]. Z Klin Med 1960;156:362–380.
13. Drachman DB, Gumnit RJ. Periodic alteration of consciousness in the “pickwickian” syndrome. Arch Neurol 1962;6:63–69.
14. Lugaresi E, Coccagna G, Mantovani M, Brignani F. Effect of tracheotomy in hypersomnia with periodic respiration. Electroencephalogr Clin Neurophysiol 1971;30:373–374.
15. Kryger M, Quesney LF, Holder D, Gloor P, MacLeod P. The sleep deprivation syndrome of the obese patient: a problem of periodic nocturnal upper airway obstruction. Am J Med 1974;56:531–539.
16. Gislason T, Almqvist M, Eriksson G, Taube A, Boman G. Prevalence of sleep apnea syndrome among Swedish men: an epidemiological study. J Clin Epidemiol 1988;41:571–576.
17. Gould GA, Whyte KF, Rhind GB, Airlie MA, Catterall JR, Shapiro CM, Douglas NJ. The sleep hypopnea syndrome. Am Rev Respir Dis 1988;137:895–898.
18. Bearpark H, Elliott L, Grunstein R, Cullen S, Schneider H, Althaus W, Sullivan C. Snoring and sleep apnea: a population study in Australian men. Am J Respir Crit Care Med 1995;151:1459–1465.
19. Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med 1998;157:144–148.
20. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163:608–613.
21. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Sleep-disordered breathing in community-dwelling elderly. Sleep 1991;14:486–495.
22. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA 2004;291:2013–2016.
23. Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284:3015–3021.
24. Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb DJ, Walsleben JA, Finn L, Enright P, Samet JM, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Intern Med 2002;162:893–900.
25. Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med 2001;164:16–30.
26. Li KK, Kushida C, Powell NB, Riley RW, Guilleminault C. Obstructive sleep apnea syndrome: a comparison between Far-East Asian and white men. Laryngoscope 2000;110:1689–1693.
27. Fogel RB, Malhotra A, Pillar G, Pittman SD, Dunaif A, White DP. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:1175–1180.
28. Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167:1181–1185.
29. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med 2003;348: 645–650.
30. Redline S, Tishler PV, Tosteson TD, Williamson J, Kump K, Browner I, Ferrette V, Krejci P. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:682–687.
31. Mathur R, Douglas NJ. Family studies in patients with the sleep apnea-hypopnea syndrome. Ann Intern Med 1995;122:174–178.
32. Pillar G, Lavie P. Assessment of the role of inheritance in sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:688–691.
33. Gislason T, Johannsson JH, Haraldsson A, Olafsdottir BR, Jonsdottir H, Kong A, Frigge ML, Jonsdottir GM, Hakonarson H, Gulcher J, et al. Familial predisposition and cosegregation analysis of adult obstructive sleep apnea and the sudden infant death syndrome. Am J Respir Crit Care Med 2002;166:833–838.
34. Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet 2005;6:221–234.
35. Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T. APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study. Neurology 2004;63: 664–668.
36. Schwab RJ, Arens R, Pack A. Sleep apnea. In: Lipson DA, van Beek EJR, editors. Functional lung imaging, lung biology in health and disease. Boca Raton, FL: Taylor & Francis Group; 2005. pp. 513–557.
37. Arens R, McDonough JM, Corbin AM, Rubin NK, Carroll ME, Pack AI, Liu J, Udupa JK. Upper airway size analysis by magnetic resonance imaging of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2003;167:65–70.
38. Gleadhill IC, Schwartz AR, Schubert N, Wise RA, Permutt S, Smith PL. Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis 1991;143:1300–1303.
39. Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 1992;89:1571–1579.
40. Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44:931–938.
41. Kubin L, Davies RO, Pack AI. Control of upper airway motoneurons during REM sleep. News Physiol Sci 1998;13:91–97.
42. Fenik P, Veasey SC. Pharmacological characterization of serotonergic receptor activity in the hypoglossal nucleus. Am J Respir Crit Care Med 2003;167:563–569.
43. Friberg D, Ansved T, Borg K, Carlsson-Nordlander B, Larsson H, Svanborg E. Histological indications of a progressive snorers disease in an upper airway muscle. Am J Respir Crit Care Med 1998;157:586–593.
44. Boyd JH, Petrof BJ, Hamid Q, Fraser R, Kimoff RJ. Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:541–546.
45. Chugh DK, Dinges DF. Mechanisms of sleepiness in obstructive sleep apnea. In: Pack AI, editor. Sleep apnea: pathogenesis, diagnosis and treatment, lung biology in health and disease. New York: Marcel Dekker; 2002. pp. 265–285.
46. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897–1904.
47. Fletcher EC, Lesske J, Qian W, Miller CC III, Unger T. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 1992;19:555–561.
48. Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 2003;167:1548–1553.
49. Veasey SC, Davis CW, Fenik P, Zhan G, Hsu YJ, Pratico D, Gow A. Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep 2004;27:194–201.
50. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med 1999;131:485–491.
51. Maislin G, Pack AI, Kribbs NB, Smith PL, Schwartz AR, Kline LR, Schwab RJ, Dinges DF. A survey screen for prediction of apnea. Sleep 1995;18:158–166.
52. Gurubhagavatula I, Maislin G, Nkwuo JE, Pack AI. Occupational screening for obstructive sleep apnea in commercial drivers. Am J Respir Crit Care Med 2004;170:371–376.
53. Flemons WW, Littner MR, Rowley JA, Gay P, Anderson WM, Hudgel DW, McEvoy RD, Loube DI. Home diagnosis of sleep apnea: a systematic review of the literature: an evidence review cosponsored by the American Academy of Sleep Medicine, the American College of Chest Physicians, and the American Thoracic Society. Chest 2003;124:1543–1579.
54. Flemons WW, Douglas NJ, Kuna ST, Rodenstein DO, Wheatley J. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med 2004;169:668–672.
55. Jenkinson C, Stradling J, Petersen S. Comparison of three measures of quality of life outcome in the evaluation of continuous positive airways pressure therapy for sleep apnoea. J Sleep Res 1997;6:199–204.
56. George CF, Nickerson PW, Hanly PJ, Millar TW, Kryger MH. Sleep apnoea patients have more automobile accidents. Lancet 1987;2:447.
57. Sassani A, Findley LJ, Kryger M, Goldlust E, George C, Davidson TM. Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep 2004;27:453–458.
58. Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002;165:670–676.
59. Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 2002;165:677–682.
60. Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE; Sleep Heart Health Study I. Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160:521–530.
61. Harsch IA, Schahin SP, Radespiel-Troger M, Weintz O, Jahreiss H, Fuchs FS, Wiest GH, Hahn EG, Lohmann T, Konturek PC, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004;169:156–162.
62. Babu AR, Herdegen J, Fogelfeld L, Shott S, Mazzone T. Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Arch Intern Med 2005;165:447–452.
63. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000;283:1829–1836.
64. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Leiby BE, Vela-Bueno A, Kales A. Association of hypertension and sleep-disordered breathing. Arch Intern Med 2000;160:2289–2295.
65. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384.
66. Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001;163:344–348.
67. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, Davies RJ. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359:204–210.
68. Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter JH. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68–73.
69. Logan AG, Tkacova R, Perlikowski SM, Leung RS, Tisler A, Floras JS, Bradley TD. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 2003;21:241–247.
70. Barnes M, Houston D, Worsnop CJ, Neill AM, Mykytyn IJ, Kay A, Trinder J, Saunders NA, McEvoy RD, Pierce RJ. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:773–780.
71. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Clin Invest 1997;99:106–109.
72. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O'Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163: 19–25.
73. Peker Y, Kraiczi H, Hedner J, Loth S, Johansson A, Bende M. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179–184.
74. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–1053.
75. Lavie L. Obstructive sleep apnoea syndrome: an oxidative stress disorder. Sleep Med Rev 2003;7:35–51.
76. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002;165:934–939.
77. Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 2003;94:179–184.
78. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–1134.
79. Imadojemu VA, Gleeson K, Quraishi SA, Kunselman AR, Sinoway LI, Leuenberger UA. Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. Am J Respir Crit Care Med 2002;165:950–953.
80. Stradling J. Con: sleep apnea does not cause cardiovascular disease. Am J Respir Crit Care Med 2004;169:148–149.
81. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. BMJ 1997;314:851–860.
82. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med 2003;163:565–571.
83. Barbe F, Mayoralas LR, Duran J, Masa JF, Maimo A, Montserrat JM, Monasterio C, Bosch M, Ladaria A, Rubio M, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness: a randomized, controlled trial. Ann Intern Med 2001;134:1015–1023.
84. Wright J, Sheldon T. The efficacy of nasal continuous positive airway pressure in the treatment of obstructive sleep apnea syndrome is not proven. Am J Respir Crit Care Med 2000;161:1776–1778.
85. Redline S, Adams N, Strauss ME, Roebuck T, Winters M, Rosenberg C. Improvement of mild sleep-disordered breathing with CPAP compared with conservative therapy. Am J Respir Crit Care Med 1998; 157:858–865.
86. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of CPAP therapy on daytime function in patients with mild sleep apnoea/hypopnoea syndrome. Thorax 1997;52:114–119.
87. Engleman HM, Kingshott RN, Wraith PK, Mackay TW, Deary IJ, Douglas NJ. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159:461–467.
88. Monasterio C, Vidal S, Duran J, Ferrer M, Carmona C, Barbe F, Mayos M, Gonzalez-Mangado N, Juncadella M, Navarro A, et al. Effectiveness of continuous positive airway pressure in mild sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001;164:939–943.
89. Mehta A, Qian J, Petocz P, Darendeliler MA, Cistulli PA. A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med 2001;163:1457–1461.
90. Fujita S, Conway W, Zorick F, Roth T. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg 1981;89:923–934.
91. Sher AE, Schechtman KB, Piccirillo JF. The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep 1996;19:156–177.
92. Li KK. Surgical therapy for adult obstructive sleep apnea. Sleep Med Rev 2005;9:201–209.
93. DePaso WJ, Weaver EM. Treating sleep apnea: continuous positive airway pressure, surgery, or dental appliances. In: Watson NF, Vaugh B, editors. Clinician's guide to sleep disorders. New York: Marcel Dekker (In press)
94. Guilleminault C, Eldridge FL, Simmons FB, Dement WC. Sleep apnea in eight children. Pediatrics 1976;58:23–30.
95. Gozal D, Burnside MM. Increased upper airway collapsibility in children with obstructive sleep apnea during wakefulness. Am J Respir Crit Care Med 2004;169:163–167.
96. McNamara F, Issa FG, Sullivan CE. Arousal pattern following central and obstructive breathing abnormalities in infants and children. J Appl Physiol 1996;81:2651–2657.
97. Gozal D. Sleep-disordered breathing and school performance in children. Pediatrics 1998;102:616–620.
98. Perez de Llano LA, Golpe R, Ortiz Piquer M, Veres Racamonde A, Vazquez Caruncho M, Caballero Muinelos O, Alvarez Carro C. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005;128:587–594.
99. Kessler R, Chaouat A, Schinkewitch P, Faller M, Casel S, Krieger J, Weitzenblum E. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001;120:369–376.
100. Nowbar S, Burkart KM, Gonzales R, Fedorowicz A, Gozansky WS, Gaudio JC, Taylor MR, Zwillich CW. Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med 2004;116:1–7.
101. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med 1995;152:1950–1955.
102. Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813–822.
103. Nachtmann A, Siebler M, Rose G, Sitzer M, Steinmetz H. Cheyne-Stokes respiration in ischemic stroke. Neurology 1995;45:820–821.
104. Bradley TD, Floras JS. Sleep apnea and heart failure: part II: central sleep apnea. Circulation 2003;107:1822–1826.
105. Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102:61–66.
106. Bradley TD, Logan AG, Kimoff RJ, Series F, Morrison D, Ferguson K, Belenkie I, Pfeifer M, Fleetham J, Hanly P, et al. for the CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025–2033.
107. Jenkinson C, Davies RJ, Mullins R, Stradling JR. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999;353:2100–2105.
Correspondence and requests for reprints should be addressed to Allan I. Pack, M.B., Ch.B., Ph.D., Center for Sleep and Respiratory Neurobiology, 125 South 31st Street, Room 2120, Philadelphia, PA 19104–3403. E-mail:


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