Obstructive Sleep Apnea: An Expert Interview With Christopher Lettieri, MD

Nancy Otto, PharmD


September 23, 2009

Editor's Note:

Obstructive sleep apnea (OSA) is an underdiagnosed debilitating condition that affects approximately 20% of adults in the United States. Characteristics of OSA include snoring and sleep arousal, mood disorders, and increased body mass index (BMI). Nancy Otto, PharmD, of Medscape interviewed Christopher Lettieri, MD, about the pathophysiology and treatment of this devastating disease.

Medscape: Dr. Lettieri, let's begin by defining obstructive sleep apnea (OSA).

Christopher Lettieri, MD: The simple definition of obstructive sleep apnea is collapse of the upper airways during sleep, resulting in airflow obstruction and repetitive arousals. Muscle tone maintains upper airway tone, so when we go to sleep our muscles relax and the caliper of our airways will narrow. For some individuals, this narrowing is significant enough to cause turbulent airflow, or snoring. Snoring by itself is not pathologic, but it suggests narrowing of the upper airways. Continued narrowing results in an obstruction of the upper airways and a cessation of airflow, which is an obstructive apneic event. Apnea is the Greek word meaning "without breath." This obstruction leads to an arousal from sleep which increases muscle tone, reestablishes airway patency, and allows normal airflow. In patients with OSA, there is a repetitive pattern of upper airway collapsibility, airflow obstruction, and resultant arousals. Thus, OSA is defined as repetitive arousals from sleep from collapse of the upper airway. Obstructive sleep apnea syndrome is OSA with more than 5 events per hour that has also some effect on either daytime function or symptoms. The most common symptom is excessive daytime sleepiness. Other consequences of OSA that would then qualify for sleep apnea syndrome include refractory hypertension, depression, and fatigue.

Medscape: What are the epidemiology and trends for OSA?

Dr. Lettieri: The first landmark study regarding the prevalence of OSA was the Wisconsin Sleep Cohort study, which identified 24% of men and 9% of women who had an apnea-hypopnea index (AHI) of at least 5 events per hour.[1] Limiting the diagnosis to those with both an AHI > 5 and excessive daytime sleepiness, they found that 4% of adult men and 2% of adult women in the United States had OSA syndrome. Since then, several additional large, population-based studies have found the prevalence of OSA to be significantly higher.[2,3,4,5]

Over the last several decades, the prevalence of OSA has been redefined. Based on several large population-based studies, it is currently estimated that at least 1 in 5 American adults has at least mild sleep apnea and 1 in 15 have moderate or severe disease.[3] There are several reasons for this increasing trend. We are an aging population and it has been clearly established that sleep apnea increases with increase in age.[3,4] In addition, there is a direct link between BMI and the occurrence of sleep apnea. So, as the average BMI continues to increase, we have and will continue to observe a progressive increase in the prevalence of OSA.

Perhaps the greatest reason for the sudden increase in the diagnosis of sleep apnea is an improved awareness by both the medical profession and the lay public. As we become aware of sleep apnea, the more we will look for it and the more we look for it, the more we find. There has been a progressive increase in the number of patients diagnosed with sleep apnea over the last decade. In fact, over this time the referrals for sleep studies have increased 12-fold and much of that is the result of increasing awareness.

Unfortunately, the majority of sleep apneics remain undiagnosed. In fact, in the Wisconsin Sleep Cohort Study, it was estimated that 93% of women and 82% of men with moderate to severe OSA are undiagnosed.[5]

Medscape: You mentioned that much of sleep apnea is undiagnosed. What are symptoms of OSA?

Dr. Lettieri: You're absolutely right -- sleep apnea largely is undiagnosed in America and there are several reasons for that. One reason is that there continues to be diagnostic profiling where OSA is only considered in obese, middle-aged men who habitually snore. This clearly is not the case and it creates a risk of missed or delayed diagnoses. Another contributing factor is that there is a narrowed focus on sleep disorders during medical school and residency, which has led to a limited understanding of these conditions among many primary care clinicians. As the field of sleep medicine advances and more patients are diagnosed with OSA and other sleep disorders, primary care clinicians will need to be able to recognize, diagnose, and treat these conditions. Patients themselves are also contributing to the underrecognition of OSA. Many may not understand or appreciate their sleep complaints or their consequences and they may not share this information with their clinicians.

Recognizing sleep complaints is often challenging for both patients and clinicians. It is very difficult to qualify or quantify purely subjective symptoms, especially excessive sleepiness. Sleepiness in one individual may be described as fatigue, exhaustion, or depression by another. As such, it is very difficult to determine who may have sleep apnea if you just focus on daytime sleepiness. There are several validated tools to help judge the severity of sleepiness, but they only weakly correlate with patients' actual subjective complaints.

Medscape: Is there a screening tool that can be used to help clinicians lead to a diagnosis of OSA?

Dr. Lettieri: The only way to truly establish the diagnosis of OSA is with polysomnography, or sleep study. The most common is an in-laboratory level 1, attended overnight study. However, recently the Centers for Medicare and Medicaid Services and the American Academy of Sleep Medicine have endorsed the use of portable monitors to establish the diagnosis of sleep apnea in a highly probable low-risk patient population.

Although a polysomnogram is required to establish the diagnosis, there are several predictive tools that can help identify patients with sleep apnea. While they each have their own strengths and limitations, they all basically focus on similar high-risk features, such as habitual snoring, witnessed apneas, an increased BMI, male gender, and advanced age. The risk for OSA increases with increased age, particularly after 50 years old. Obesity and surrogate markers of obesity also increase the probability for OSA. In particular, a BMI greater than 30, a neck circumference greater than 15.5 inches, or truncal obesity are strongly associated with the risk of OSA.[6] Crowding of the oropharynx can also help identify those with OSA. An increased Mallampati score, macroglossia, retrognathia, and micrognathia lead to oropharyngeal crowding, which increases the likelihood of collapsibility of the upper airway and obstruction to airflow during sleep. However, these predictive rules and high-risk features have only modest sensitivity and specificity for OSA. One validated tool which can help identify those with OSA is the STOP BANG questionnaire (Snoring, Tired, Observed apneas, high blood Pressure, BMI > 30 kg/m2, Age > 50, Neck circumference 15.5 inches, male Gender).[6] Simply, the more features a patient has, the greater the pretest probability they have OSA, with sensitivities of 83.6%, 92.9%, and 100% for mild, moderate, and severe sleep apnea, respectively. While useful, it has high false-positive and false-negative rates and, as with all predictive rules, should not replace clinical judgment. When there is a high clinical suspicion for OSA, the patient should be referred for polysomnography to confirm the diagnosis.

In addition to somnolence, increased weight, age, snoring, and witnessed apneas, there are several other prevalent features seen with OSA that are often overlooked. These include:

  • Sleep fragmentation and poor sleep quality;

  • Night sweats;

  • Nocturnal reflux;

  • Nocturia;

  • Progressive weight gain;

  • Depression;

  • Diminished libido or erectile dysfunction;

  • Poor memory or attention;

  • Irritability and moodiness;

  • Fatigue; and

  • Underlying cardiovascular disease, particularly hypertension.

Medscape: Who are the clinicians that treat sleep apnea? When should patients be treated in primary care, and when is referral to a specialist appropriate?

Dr. Lettieri: Currently, sleep medicine specialists are involved in establishing the diagnosis, initiating therapy, and providing follow-up for the majority of patients with OSA. However, as with other common medical conditions, this is a disease that is rapidly transitioning to primary care clinicians. As I mentioned, sleep apnea occurs in one fifth of the adult population and is largely underdiagnosed and undertreated. As the prevalence of OSA increases, it will quickly overwhelm the clinical sleep medicine community and much of the burden for diagnosing and treating this condition will be the responsibility of primary care clinicians. We are already seeing, and will continue to see, family medicine clinicians, internal medicine clinicians, and even pediatricians make the diagnosis and provide care for patients with OSA. I anticipate that in the future, sleep medicine specialists will likely be utilized to help establish the diagnosis and treat more severe cases or people who are poorly adherent with therapy, while the majority of patients will be primarily managed by primary care clinicians.

It is imperative that primary care clinicians become more familiar with sleep apnea. Not only is it a common disorder, but if sleep apnea is overlooked or the diagnosis delayed, it can lead to long-term health consequences and the propagation of sleep apnea. The earlier it is diagnosed the better. Part of the residual hypersomnia that occurs despite adequate therapy is related to the duration of untreated sleep apnea, the severity of the disease, and the severity of nocturnal hypoxia. The longer it takes to diagnose and treat sleep apnea, the less likely it is that the daytime somnolence will resolve. In addition, once established, endothelial dysfunction and metabolic derangements seen with OSA are also less likely to resolve with CPAP [continuous positive airway pressure].

Medscape: What are the consequences of OSA?

Dr. Lettieri: The more we understand about sleep apnea, the more we realize how it impacts health and quality of life. In regards to quality of life, we know that sleep apnea causes excessive sleepiness, fatigue, and decreased energy. Anything that disrupts sleep quality can lead to excessive sleepiness or fatigue during the day. Additionally, irritability, moodiness, and depression are very prevalent in patients with untreated sleep apnea. In a study by Peppard and colleagues,[7] there was a twofold increased risk of depression in patients with mild OSA and a 2.6-fold increased risk for depression in those with moderate or severe disease.

Not only does OSA impair quality of life, it also adversely affects health, with numerous metabolic and cardiovascular consequences. Metabolic consequences are common in patients with sleep apnea. These occur not only from the disruptive sleep architecture and poor sleep quality, but also from an increased sympathetic tone that results from repetitive arousals. OSA may result in increased insulin levels and cortisol secretion, leading to elevated serum glucose levels and the development of insulin resistance. In addition, there is an imbalance in leptin and ghrelin, hormones which regulate satiety and hunger. This leads to an imbalance in lipogenesis and lipolysis where patients become more efficient at storing fat than utilizing fat, which leads to more weight gain and further propagation of OSA. There are several overlapping risk factors for both OSA and diabetes (eg, excessive body weight). However, there is increasing evidence that OSA is independently associated with impaired glucose tolerance, insulin resistance, and the metabolic syndrome.[8]

The repetitive arousals seen in OSA can lead to episodic catecholamine surges and an elevated sympathetic tone. This elevated sympathetic tone with the intermittent hypoxia associated with apneic events can cause endothelial dysfunction with resultant hypertension and accelerated atherosclerosis. Hypertension is extremely common in patients with OSA and occurs in up to 50% of individuals. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)[9] lists OSA as the most common cause of secondary hypertension in the US. In 2 large case series, OSA was found in 11%-37% of patients with heart failure.[10] There is also an increased risk of myocardial infarctions and cerebrovascular accidents with a clear, dose-response relationship between the severity of sleep apnea and the likelihood of a cardiovascular event.[11,12]

People with untreated sleep apnea have an increased all-cause mortality rate. In one study of patients with moderate to severe sleep apnea, the 5-year risk of death was 14% in those who refused continuous positive airway pressure vs 4% in those complaint with therapy.[13] Another study found that over a 14-year period, the all-cause mortality associated with moderate to severe sleep apnea was 33% compared with only 7.7% in those without OSA.[14] It could be argued that the same risks for OSA and its associated features (ie, older age, male gender, obesity, hypertension) are the reason we are observing an increased risk of cardiovascular events and death. However, Yaggi and colleagues[11] found that patients with OSA had a significantly increased risk compared with controls. In this study, the hazard ratio was 1.97 after adjusting for factors such as hypertension and diabetes.

Medscape: While you were discussing the consequences, you mentioned CPAP as one of the treatments. Can you tell us more about the treatments for OSA?

Dr. Lettieri: There are 4 therapies for OSA. One is conservative therapy, which includes weight loss, positional therapy, and treatment of chronic sinus disease, which are all helpful for improving sleep quality and even reducing the severity of OSA. As I mentioned, there is a clear association with weight gain and OSA, and the more weight you gain the worse your sleep apnea becomes. Weight loss will decrease the severity of sleep apnea, but unfortunately it's not a linear relationship. Patients are unlikely to reduce the severity of sleep apnea proportionate to the amount of weight lost, but all weight loss does help. If the patient has mild sleep apnea, it may be enough to resolve their obstructive events. However, most patients have residual OSA despite weight loss. In a recent study and subsequent meta-analysis performed in our lab, we found that significant weight loss did reduce the severity of OSA, but the majority of individuals had persistent disease.[15,16]

Between 10% and 30% of patients will have a large positional component to their sleep apnea. As mentioned, the pathogenesis of sleep apnea is collapsibility of the upper airway. In the supine position, gravity contributes to the subluxation of the oropharynx and makes upper airway obstruction more likely. Sleeping on one's side or elevating the headboard by 2-4 inches can offload some of the effects of gravity on the upper airway and reduce the severity of sleep apnea. For some people, particularly those with mild OSA, and especially those with a large positional component, forced sleep in the lateral position can be enough to normalize sleep architecture and decrease apneic events.

Sinus congestion actually goes hand in hand with OSA. OSA can cause vasomotor rhinitis. As apneic patients struggle to get air in, the resulting increased upper airway resistance that occurs can cause inflammation of the upper airways. Sinus congestion in and of itself can cause sleep fragmentation and daytime somnolence. For those with concomitant OSA, it can decrease the efficacy and comfort of CPAP. As such, chronic rhinitis should be treated when present.

Conservative therapy should be employed in all patients. However, while they are helpful, they are usually not sufficient to resolve sleep apnea enough to normalize sleep. Three forms of directed therapy are usually recommended for all patients with sleep apnea syndrome: CPAP, oral appliances, and surgery.

Oral appliances are either fixed or titratable devices that advance the mandible to prevent subluxation of the tongue and oropharyngeal collapse. These devices can be very effective in certain patients. They are usually better for those with mild and potentially moderate sleep apnea, and there is some success in people with severe disease. When they are effective, they represent a very good treatment option for people with sleep apnea. They are limited by temporomandibular joint discomfort and malocclusion of the teeth, especially over time.

Surgery can be an effective [treatment] for sleep apnea. There are different surgical techniques. Some of those are better for snoring than they are for sleep apnea, such as the uvulopalatopharyngoplasty. In correctly selected patients, approximately 50% of people will have a 50% reduction in the apnea-hypopnea index. However, patients with moderate to severe sleep apnea are often left with residual disease despite what is considered to be a successful surgery. Some other surgical techniques such as genioglossus advancement or maxillomandibular osteotomy can be very effective, especially if performed as staged procedures. However, any surgical procedure is associated with inherent risks and the possibility that it will not resolve OSA and should only be performed in properly selected patients. Typically, surgery should be reserved for patients who are intolerant of CPAP.

CPAP is the most effective and most widely used treatment for OSA, and approximately 95% of people will have a 90%-95% reduction in their apnea hypopnea index. For the vast majority of people, this provides adequate therapy. CPAP delivers a column of air that acts as a pneumatic splint to hold open the upper airways and prevent collapsibility and closure. While extremely effective, CPAP does not offer a cure, but merely a treatment. Therefore, if people don't use their CPAP, they have untreated sleep apnea. Although effective, adherence with therapy remains problematic. Patients often struggle with compliance because CPAP requires an interface with a mask that pushes a column of air into the upper airway passage. This can be uncomfortable for patients, especially in the initial treatment period where they are learning to adjust and sleep with their CPAP. Often we see this negative conditioning response where people will initially be intolerant of CPAP. Unfortunately, this initial discomfort may lead to an abandonment of therapy, and most people who discontinue CPAP will do so within the first month. In fact, long-term compliance is often predicted very early in the course of therapy, often within the first few weeks or perhaps even in the first few days of CPAP use. Those who adapt to the CPAP quickly will often continue to use it long-term, and those who struggle initially will often abandon therapy. About 50% of people who start CPAP will not use it 1 year later. Despite being a very effective and cost-effective treatment for sleep apnea, adherence to CPAP therapy remains problematic. Interventions that improve the initial experience with CPAP have been shown to improve long-term use, such as better mask fitting, comprehensive patient education, and a short course of sedative-hypnotics during the initial treatment period.

Medscape: We haven't discussed pharmacologic treatment. Are there any pharmacologic therapies that can help sleep apnea?

Dr. Lettieri: A few agents have been studied, but none have been shown to be very effective. One of the problems with sleep apnea is the sleep fragmentation and the repetitive arousals from sleep. Sedative-hypnotics can decrease some of the arousals and sleep fragmentation that occurs with sleep apnea. Of course they do not prevent airway closures or stop the apneic event, so patients will still have sleep apnea. While this doesn't fix the primary problem of sleep apnea, it may provide some better sleep continuity and some decrease in sleepiness during the day. Of course these medications should not be used as the sole treatment for sleep apnea because they do not resolve the underlying pathophysiologic cause or consequence of sleep apnea.

We know that sleep apnea is not the same throughout the course of the night. It tends to be worse in certain stages of sleep, especially in rapid-eye-movement (REM) sleep. REM sleep induces skeletal muscle atonia, making the upper airways more susceptible to collapse. Agents that suppress REM sleep, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors can reduce the severity of sleep apnea. Again, these agents do not resolve sleep apnea completely, and over time they have less effect on REM suppression. Also, these medications are associated with sleep fragmentation and may cause excessive daytime sleepiness. Therefore, they do not provide an effective long-term solution. They may be a reasonable alternative in patients as either an adjunctive therapy to CPAP or in patients with very mild and REM-specific sleep apnea.

Non-amphetamine based stimulants, including modafinil (Provigil®) or armodafinil (Nuvigil®) are approved by the US Food and Drug Administration as adjunctive therapy to CPAP in patients with residual daytime sleepiness despite adequate therapy. While I mentioned CPAP is the most effective therapy that we have for sleep apnea, a third of patients will have residual subjective sleepiness and up to two thirds of patients have residual objective sleepiness despite good adherence with CPAP therapy.[17] OSA, particularly moderate to severe disease associated with significant nocturnal hypoxia, can cause neurocognitive dysfunction that may be irreversible and lead to persistent somnolence despite adequate therapy. For patients who have persistent hypersomnia despite adequate CPAP therapy, both modafinil and armodafinil have been shown to be extremely effective in improving quality of life and daytime function and reducing both objective and subjective sleepiness.[18,19] However, they should not be used as the primary treatment, but reserved for those who have residual somnolence despite adherence with CPAP.

Medscape: You mentioned the link between BMI and sleep apnea. Can you tell us more about this relationship?

Dr. Lettieri: There is a clear association with sleep apnea and BMI. Excessive weight can cause or precipitate OSA and OSA can lead to weight gain. In short, there is a vicious cycle between OSA and weight gain. Weight gain tends to cause a deposition of fat in the upper airways, which narrows oropharyngeal patency. The more weight you gain, the worse your sleep apnea becomes. The prevalence of OSA is at least 90% in morbidly obese individuals. Not only is OSA more prevalent, but disease severity is usually worse and the oxygen nadir at night is much lower.

Like all causes of poor sleep or sleep deprivation, OSA by itself promotes weight gain. Sleep disorders create an imbalance of leptin and ghrelin and tend to elevate cortisol levels, which helps to promote more weight gain. So it's not necessarily a function of caloric intake and exercise, but rather hormone-mediated weight gain that leads to this cycle seen in OSA. Since weight gain causes or worsens sleep apnea, it would make sense that weight loss would reduce the severity of sleep apnea, and it clearly does. The problem is that except for mild sleep apnea, patients are unlikely to resolve OSA with weight loss. And patients with untreated sleep apnea may have difficulty losing weight because of the hormonal imbalance I mentioned. Even significant weight loss, especially in those with moderate to severe disease, may not resolve OSA completely. A recent meta-analysis assessing the effect of bariatric surgery on OSA concluded that the majority of patients with OSA had persistent disease despite very significant weight loss.[16] Weight loss offers numerous benefits to both health and quality of life and should be encouraged in all patients, especially those with OSA, as it will also reduce disease severity. However, patients should not assume that even significant weight loss has resolved their apneic events. Doing so creates a risk of unrecognized and untreated disease that can result in a re-accumulation of weight as well as the other adverse effects on health and quality of life previously mentioned.


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