Sleep Apnea

Sleep Apnea

1 Overview

Summary and Quick Facts

  • Sleep apnea is breathing interruptions during sleep. These interruptions cause us to wake up numerous times during the night. Sleep apnea is linked to heart disease, diabetes, poor cognitive function and many other health concerns.
  • In this protocol, learn about the different kinds of sleep apnea and why it is so important to have it properly diagnosed and treated. Also learn about lifestyle and dietary habits that may help improve it. Dietary supplements that address some of the factors that contribute to sleep apnea will be reviewed, as well.
  • Effective sleep apnea treatments are available, and they can greatly improve quality of life. But many people either don’t seek treatment or give up quickly due to inconvenience or discomfort. It’s important to work with a qualified sleep specialist to find the right solution for you, which may take trial and error.

Sleep apnea is an increasingly common but underdiagnosed disorder characterized by repeated pauses in breathing during sleep that can lead to the following serious health problems:

  • cardiovascular disease
  • type 2 diabetes
  • cancer
  • gout
  • cognitive dysfunction
  • increased risk of dying from any cause

Fortunately, integrative interventions like N-acetyl-cysteine (NAC) and coenzyme Q10 can improve sleep quality and respiratory function in patients with sleep apnea.

Risk Factors for Developing Sleep Apnea

  • Overweight and obesity
  • Smoking
  • Allergies and asthma

Signs and Symptoms Associated with Sleep Apnea

  • Snoring
  • Pauses in breathing
  • Intermittent waking and insomnia

Conventional Medical Treatments

  • CPAP (continuous positive airway pressure)
  • Other oral appliances to help keep the upper airway open  
  • Surgery for when the obstruction is due to an anatomical problem, such as enlarged tonsils or adenoids  

Novel and Emerging Therapies

  • Estrogen and progesterone for women
  • Hypoglossal nerve stimulation
  • Renal denervation
  • Nasal continuous positive airway pressure and oral pressure therapy

Dietary and Lifestyle Changes

  • Obesity is the most important major modifiable risk factor associated with obstructive sleep apnea; therefore, weight loss is an important intervention.
  • Exercising 2.5‒4 hours per week may reduce severity and symptoms of sleep apnea even without weight loss.

Integrative Interventions

  • N-Acetyl-Cysteine (NAC): NAC has mucus-reducing properties that have been shown to cause significant improvements in measurements of apnea severity and sleep quality.
  • Vitamin C: Improves endothelial health of sleep apnea patients and reduces episodes of sleep apnea and daytime sleepiness along with vitamin E.
  • Vitamin E: Shown to reduce episodes of sleep apnea and daytime sleepiness along with vitamin C as well as improve respiratory function in combination with other antioxidants.
  • Coenzyme Q10 (CoQ10): Improves respiratory function in combination with other antioxidants in patients with sleep apnea. Patients with sleep apnea are at increased risk for cardiovascular disease, and CoQ10 supplementation may confer a benefit in cardiovascular disease.
  • Selenium: Patients with lower red blood cell selenium levels were found to have more severe sleep apnea, as measured by the apnea-hypopnea index.

2 Introduction

Sleep apnea is an increasingly common and often overlooked disorder characterized by repeated pauses in breathing during sleep (Jordan 2014; Hayes 2014; Strohl 2013). These frequent respiratory pauses result in periods of low blood oxygen levels, nervous system dysfunction, and sleep fragmentation, leading to an array of serious health problems. In fact, an abundance of research shows that sleep apnea considerably increases the risk of dying from any cause (Panossian 2013; Kendzerska 2014).

Sleep apnea is an under-recognized but growing epidemic with alarming public health implications. The National Sleep Foundation estimates that more than 18 million people in the United States have sleep apnea, but this insidious condition is believed to be vastly underdiagnosed (NSF 2014; Ramirez 2013; Paiva 2014; Yu 2011; Peppard 2013; Hayes 2014; Motamedi 2009).

There are many consequences of untreated sleep apnea, including the hallmarks of chronic sleep deprivation: daytime sleepiness, cognitive difficulties, depression, and increased risk of accidents and injuries (Seneviratne 2004; Hayes 2014; NSF 2014; Thompson 2012; NIH 2006; Ellen 2006; Findley 1991; Mayo Clinic 2012). In addition, a significant and growing list of serious chronic ailments have been associated with sleep apnea, including cardiovascular and neurological diseases, pregnancy complications, obesity, bleeding peptic ulcers, and insulin resistance and type 2 diabetes (Paiva 2014; Jordan 2014; UMMC 2013b; Mirrakhimov 2013; Hayes 2014). Researchers are also investigating possible associations between sleep apnea and autoimmune diseases, osteoporosis, and even cancer (Kang 2012; Mirrakhimov 2013; Yen 2014; Noguti 2013; Pamidi 2014).

The first-line treatment approach for obstructive sleep apnea is a device that provides continuous positive airway pressure, known as CPAP (NSF 2014; Hayes 2014). The device is worn during sleep and introduces mildly pressurized air into the airways to keep them open (Mayo Clinic 2012; NSF 2014). The benefits of CPAP are particularly evident in those with sleep apnea who experience excessive daytime sleepiness (Chiner 2013). Moreover, research suggests CPAP use might improve markers of cardiovascular health and glucose metabolism for those with sleep apnea (Monahan 2011; Gottlieb 2014; Gallegos 2014; Chen, Pei 2014; Schlatzer 2014; Ayas 2006).

Some patients are unable to tolerate CPAP, in which case other therapies may be considered. Dental devices and surgical procedures to open the airway may be beneficial in some people with sleep apnea. Other methods sometimes recommended include bariatric weight loss surgery and negative pressure devices (Freedman 2014; Hayes 2014).

Dietary and lifestyle interventions can have a significant impact on the severity and consequences of sleep apnea. Weight loss is the most common and well-supported adjunct to CPAP, and it can be effective on its own (Hayes 2014; UMMC 2013a; Thompson 2012). Exercise, even without weight loss; correct sleep position; avoidance of alcohol and sedatives before bed; and a generally healthy diet are important for managing sleep apnea (UMMC 2013b; Hayes 2014). Integrative interventions may both reduce the severity of sleep apnea and help minimize the consequences of some of the serious conditions associated with sleep apnea (Grebe 2006; Singh 2009; Sadasivam 2011; Lee 2009).

In this protocol, you will learn about the causes of sleep apnea and factors that increase sleep apnea risk. Conventional treatment approaches will be reviewed, as will several novel and emerging treatment strategies. A number of lifestyle considerations and natural, integrative interventions that may lessen the impact of sleep apnea will be discussed as well.

3 Background

Sleep apnea is divided into two types: obstructive and central, with obstructive being much more common (UMMC 2013a; NSF 2014). In obstructive sleep apnea, the airways collapse and block airflow episodically during sleep. In central sleep apnea, the respiratory control centers in the brain do not provide sufficient stimulation to maintain regular breathing during sleep. However, it appears that elements of both obstructive and central mechanisms occur simultaneously in some people with sleep apnea (Ramirez 2013; Khan 2014; ASAA 2014; Hoffman 2012; Lehman 2007).

Obstructive Sleep Apnea

Swelling, narrowing, or anatomical abnormalities of structures of the air passageway can obstruct airflow, causing a pause in respiration that must be overcome by strong signals from the brain’s respiratory center to trigger inhalation (Jordan 2014; Schwab 2011; ATS 2014). Posture often plays a crucial role in obstructive sleep apnea; the gravitational pull associated with a back-sleeping position can cause an increased tendency for the airway to collapse and block airflow (Bilston 2014).

Central Sleep Apnea

The involuntary breathing reflex is regulated by the brain in response to blood carbon dioxide levels. Normally, as blood carbon dioxide levels rise, the respiratory center of the brain triggers increased breathing (Nattie 1999; Guyton 1990). In central sleep apnea, the brain does not adequately regulate breathing. Central sleep apnea is often caused by another health condition. For instance, central sleep apnea is common in congestive heart failure and with chronic opioid drug use (Javaheri 2013; Floras 2014). Central sleep apnea can also occur without a clear cause (Ramirez 2013; ASAA 2014).

Mixed or Complex Sleep Apnea

Mixed sleep apnea, sometimes referred to as complex sleep apnea, involves both obstructive and central components. Up to18% of people with sleep-disordered breathing—the broad category that includes apneas as well as less severe hypopneas (shallow and/or slow breathing)—may have mixed sleep apnea. In a significant percentage of cases, central apnea is revealed during treatment of the obstructive aspect of sleep apnea with CPAP (Khan 2014; Hoffman 2012; Lehman 2007).

Association with Other Diseases

Sleep apnea is associated with a number of serious conditions (Thompson 2012; Martinez Ceron 2014; Yu 2011; Canales 2008):

Cardiovascular disease. Intermittent hypoxia (periods of low oxygen levels) caused by sleep apnea can contribute to chronic high blood pressure and endothelial damage (Ziegler 2011). People with obstructive sleep apnea are more likely to suffer from high blood pressure, coronary artery disease, and abnormal heart rhythms, and they have a higher risk of heart failure, heart attack, and stroke (Jean-Louis 2008; Gottlieb 2013; Pepin 2014; Ali 2014; Hohl 2014; Oldenburg 2014).

Type 2 diabetes and obesity. Up to 40% of people with obstructive sleep apnea have type 2 diabetes, and as many as 53% of overweight or obese people with type 2 diabetes have obstructive sleep apnea (Bonsignore 2013; Nannapaneni 2013). Sleep apnea is also independently associated with insulin resistance (Martinez Ceron 2015). Obesity in general, and especially abdominal or central obesity, is a major risk factor for obstructive sleep apnea (Hoffstein 1992; Schwartz 2008; Thompson 2012; Stadler 2009; Hayes 2014).This relationship between obesity and obstructive sleep apnea appears to be bidirectional. While obesity likely plays a causal role in obstructive sleep apnea, sleep apnea may contribute to weight gain (Romero-Corral 2010; Pillar 2008; Yu 2011).

Cancer. In a study that followed 386 adults over 20 years, moderate-to-severe obstructive sleep apnea was associated with a 2.5 times higher risk of new cancer diagnosis and a 3.4 times higher risk of cancer death (Marshall 2014). In another study, individuals with mild sleep disordered breathing (SDB) had 1.1 times the risk of dying of cancer, those with moderate SDB had 2 times the risk, and those with severe SDB had 4.8 times the risk, compared with healthy subjects (Nieto 2012).

Gout and hyperuricemia. Gout is a painful arthritic condition caused by an excess of uric acid in the blood (hyperuricemia), which accumulates as crystals in the joints (NLM 2014). People with gout appear to be at increased risk of sleep apnea (Roddy 2013). Furthermore, individuals with high uric acid levels have been shown to be more likely to snore more than five nights per week and to experience daytime sleepiness (Wiener 2012). Uric acid level is known to rise in concert with increasing frequency of apneic episodes and has been suggested to be a marker of sleep apnea severity (Cantalejo Moreira 2013; Hirotsu 2013; Kanbay 2014; Wiener 2012).

Cognitive and neurological problems. Studies suggest chronic sleep deprivation and interruption may increase the risk of chronic cognitive problems and neurological disease, including Alzheimer’s disease (Lucey 2014; Buratti 2014).

Pregnancy complications. Obstructive sleep apnea is common in pregnancy, and symptoms associated with sleep apnea such as snoring generally worsen as pregnancy progresses (Sarberg 2014; Calaora-Tournadre 2006; Facco 2012; Sahota 2003; Lefcourt 1996). A rigorous scientific literature analysis concluded that, in pregnant women, sleep disordered breathing—a designation for a group of related conditions that includes sleep apnea—is associated with a 2.34-fold increased risk of gestational high blood pressure and a 1.86-fold increased risk of gestational diabetes compared with those without sleep apnea (NIDDK 2013; NLM 2015b).

Erectile dysfunction. It has been estimated that half of men with sleep apnea also have erectile dysfunction, and vice versa. This association could be explained by dysfunction of the cells lining the insides of blood vessels (endothelial dysfunction), a condition common to both erectile dysfunction and obstructive sleep apnea (Hoyos, Melahan, Phillips 2014).

Low testosterone levels. Several studies have confirmed that serum testosterone levels are lower in men with obstructive sleep apnea. A study that compared 36 men with stable mild-to-severe obstructive sleep apnea to healthy controls found that lower serum testosterone levels were associated with greater sleep apnea severity and body mass index (Canguven 2010). One study found that men with obstructive sleep apnea had 17% lower serum testosterone levels than controls (Bercea 2014); another found that obese men with severe obstructive sleep apnea had significantly lower testosterone levels than matched, healthy controls, and that lower testosterone was significantly correlated with symptoms of depression in the obstructive sleep apnea group (Bercea 2013).

Systemic conditions. Obstructive sleep apnea and accompanying intermittent hypoxia are associated with increased oxidative stress, systemic inflammation, and endothelial dysfunction (Alzoghaibi 2012; Badran 2014; Nadeem 2013; Chen 2013; Hoyos, Melehan, Liu 2014; Drager 2013; Ziegler 2011).

Other conditions. In a five-year study following 1411 people with obstructive sleep apnea and 7055 without, obstructive sleep apnea was associated with 1.9 times the risk of developing an autoimmune disease (Kang 2012). Obstructive sleep apnea has also been associated with depression, glaucoma, interstitial cystitis, and chronic kidney disease (Chung 2014; Lin 2011; Perez-Rico 2014; Cross 2008; Dantzer 2008; Adeseun 2010; Chou 2011).

4 Risk Factors

Overweight and Obesity

Obesity is the clearest risk factor for obstructive sleep apnea. However, patterns of fat distribution may affect men and women differently. In 151 patients undergoing sleep studies, neck and waist circumference, and waist-to-hip ratio were evaluated. In men, neck circumference and waist-to-hip ratio were significantly associated with the apnea-hypopnea index, a measure of sleep apnea severity. In women, only waist-to-hip ratio was significantly associated with apnea-hypopnea index (Lim 2014; Ayas 2014).

Smoking

Smoking increases the risk of obstructive sleep apnea, and of developing obstructive sleep apnea at an earlier age than people who never smoked. Cigarette smoking increases upper airway resistance as a result of inflammation, swelling and increased mucus secretion, which may explain this association (Boussoffara 2013; Hizli 2013; Quan 2014; Lin 2012).

Allergies and Asthma

In a study in over 1900 individuals, the combination of asthma and allergic rhinitis was associated with 1.44-fold increased odds of obstructive sleep apnea compared to those with just asthma. When allergic rhinitis duration and severity were taken into account, the odds rose to 1.99-fold. The authors concluded that allergic rhinitis, independent of obesity and other risk factors, contributes to the risk of sleep apnea (Braido 2014).

Gender and Ethnicity

Men are at twice the risk of obstructive sleep apnea compared with women (Sutherland 2012; Valipour 2012). African American men under age 39, and between 50 and 59, have more severe sleep apnea compared with white men of the same age (Pranathiageswaran 2013; Sutherland 2012). In Asians, the association of obstructive sleep apnea with obesity is not as strong as in other ethnicities (Chirakalwasan 2013).

Age

The risk of sleep apnea increases with age. This may be due to factors such as diminished efficiency of muscles and soft tissues in the upper airway or reduced sleep quality (Jordan 2014).

Declining Hormone Levels (in Women)

The risk of sleep apnea increases significantly after menopause, and some evidence suggests female reproductive hormones play a protective role against obstructive sleep apnea (Dursunoglu 2009; Tamanna 2013; Keefe 1999; Dancey 2001; Tasali 2008). Indeed, a preliminary study showed that estradiol plus progestin therapy or estradiol alone reduced the severity of sleep apnea in five postmenopausal women (Keefe 1999).

Family History and Narrow Airways

Obstructive sleep apnea may have a hereditary component, perhaps because its risk factors also run in families (Hayes 2014; Thompson 2012). These include anatomical features of the airway and obesity (Redline 1995; Jordan 2014).

5 Signs and Symptoms

Sleep apnea often goes undiagnosed largely because the direct symptoms are witnessed only by bedmates, and the indirect symptoms, those related to sleep deprivation, can be vague or attributable to many possible causes (Ho 2011). The most common sleep apnea symptoms include (Lal 2012; Mayo Clinic 2012; Karacan 1995):

  • Snoring. Loud snoring often indicates the presence of sleep apnea, and it is more pronounced in obstructive sleep apnea. Apneas may also interrupt snoring and cause the patient to snort.
  • Pauses in breathing. Sleep apnea often causes pauses in breathing during sleep that are noticed by another person. Someone with sleep apnea may pause breathing for a period during sleep then gasp for air.
  • Intermittent waking and insomnia. It may be difficult to remain asleep. Patients may also awake suddenly with shortness of breath.
  • Dry mouth, sore throat, and headache upon waking.
  • Fatigue and excessive daytime drowsiness. Patients with sleep apnea are susceptible to falling asleep at work and while driving.
  • Attention, learning and memory difficulties. This can include difficulty concentrating, reasoning, and paying attention. 
  • Feeling moody, depressed, or irritable.
  • Sexual dysfunction. Lack of libido and impotence are common concerns in people with sleep apnea.

6 Diagnosis

Screening

Given the high prevalence of sleep apnea and its association with serious health conditions, simple clinical screening for obstructive sleep apnea in high-risk groups is important. Symptoms such as snoring, excessive daytime sleepiness, and reports of sleep disordered breathing accompanied by obesity, cardiovascular disease, type 2 diabetes, or metabolic syndrome are likely to indicate candidates for further screening or intervention (Seetho 2013). Before diagnosing sleep apnea, physicians must rule out a number of other conditions that can cause similar symptoms (Gutierrez 2013).

Various screening questionnaires have been developed in order to predict the existence and severity of obstructive sleep apnea, as well as the likelihood of clinical complications of obstructive sleep apnea in pre-surgical and hospital settings. One of the most well validated is STOP-BANG, which stands for “Snoring, Tiredness during daytime, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender” (Braido 2014). A STOP-BANG score of three or more (out of eight) is a sensitive indicator of obstructive sleep apnea, while a score of six out of eight is a highly specific indicator of severe obstructive sleep apnea (Chung 2013; Proczko 2014; Chung 2012; Silva 2011).

Testing

The definitive test for sleep apnea is an overnight polysomnography, often called a sleep study. This test is done in a laboratory and monitors the occurrence of apneic (paused) and hypopneic (shallow and/or slow) breathing episodes by measuring respiratory effort, airflow, and blood oxygen saturation. Polysomnography also includes neurological testing to monitor limb movements, body position, and the sleep-wake state (Jordan 2014).

The accepted criterion for a diagnosis of sleep apnea is five or more episodes of apnea or hypopnea per hour lasting for 10 or more seconds each. Diagnosis of mild, moderate, or severe sleep apnea is based on clinical presentation and sleep study results (De Backer 2013).

American Academy of Sleep Medicine Obstructive Sleep Apnea Classifications (Gutierrez 2013)


Classification

AHI*

Clinical presentation and associated risks

Mild**

5–15 episodes per hour

  • Mild sleepiness or insomnia
  • Mildly low oxygen levels
  • Benign cardiac arrhythmias

Moderate

15–30 episodes per hour

  • Moderate daytime sleepiness, fatigue that interferes with normal daily activities
  • Moderately low oxygen levels and/or mild cardiac arrhythmias
  • At risk for injuries/accidents
  • At risk for high blood pressure, heart attack, stroke and right-sided heart failure

Severe

>30 episodes per hour and/or hypoxia <90% for >20% of total sleep time

  • Daytime sleepiness interferes with normal daily activities
  • Severely low oxygen levels
  • Moderate-to-severe cardiac arrhythmias
  • At risk for injuries/accidents
  • At significant risk for high blood pressure, heart attack, stroke, and right-sided heart failure

*AHI, apnea-hypopnea index
** Patients with mild obstructive sleep apnea (ie, 5–15 episodes per hour) may be asymptomatic.

Because polysomnography is cumbersome, expensive, and inconvenient, portable monitoring devices are sometimes used in the home to aid in diagnosis. Two examples of portable devices that have been found comparable to polysomnography, and which, in the future, may be useful as stand-alone diagnostic tools, are a portable pulse oximeter, which can attach to a finger and non-invasively measure oxygen saturation as it rises and falls during sleep (Romem 2014), and a peripheral arterial tonometer, which measures changing vascular tone (Yalamanchali 2013).

7 Conventional Treatments

CPAP: Continuous Positive Airway Pressure

CPAP is first-line treatment for obstructive sleep apnea (Phillips 1990; Elshaug 2008; Almeida 2013). Numerous studies show that this method of applying constant mild air pressure to the airway during sleep reduces apneic (paused) and hypopneic (light) breathing and helps relieve signs and symptoms of sleep loss like fatigue, drowsiness, and cognitive and mood changes (Weaver 2012; Engleman 1993; Sanchez 2009; Kushida 2012; Ferini-Strambi 2003; Tomfohr 2011; Lau 2013). A 2013 review indicates that the more hours per night the device is used, the greater the benefit (Wickwire 2013).

Several studies have found that treatment of sleep apnea with CPAP can improve cardiac function and insulin sensitivity; and reduce heart rate, blood pressure, and cardiovascular mortality (Hassaballa 2005; Fava 2014; Aggarwal 2014; Ge 2013; Cordero-Guevara 2011; Marin 2005). An analysis of prior research found a trend for CPAP use to reduce the risk of death due to cardiovascular events in people with sleep apnea (Ge 2013).

There have been mixed results in studies looking at the effect of CPAP on blood glucose control, but it appears that people with severe sleep apnea are the most likely to experience a benefit in blood glucose management with CPAP (Bonsignore 2013). A rigorous review of studies examining CPAP and glycemic control concluded that most studies show that CPAP improves insulin sensitivity and markers of long-term glucose control in people with sleep apnea and type 2 diabetes or pre-diabetes. The best effect was seen after three months of nightly use for four or more hours per night (Gallegos 2014).

One barrier to consistent CPAP use is comfort (Beecroft 2003; Ballard 2007; Weaver 2010). It is estimated that only 70% of people to whom CPAP is recommended actually begin treatment with it, and of those who do, only 50% continue long term. Furthermore, many people are unsuccessful at using CPAP for the recommended number of hours during sleep. Fortunately, technological advances intended to improve patient comfort are under development (Wickwire 2013).

People who tolerate the CPAP mask and straps but find the constant air pressure uncomfortable may prefer one of two other options for positive airway pressure. The first is called bilevel positive airway pressure, or BiPAP. With BiPAP therapy, a lower level of air pressure is used during expiration, and a higher level during inspiration. This may improve comfort, especially for people who use higher pressure settings with CPAP and have trouble exhaling against the pressure. The second is called automatic positive airway pressure, or APAP. With APAP therapy, the device automatically adjusts its pressure output to the pressures it senses during the breathing cycle. APAP may be more comfortable for people whose apnea occurs mainly in certain sleep positions (Stasche 2006).

Other Oral Appliances

Oral appliances, or dental devices, are used during sleep to physically keep the upper airway open by either holding the lower jaw forward or moving the tongue forward (Hoffstein 2007; Chan 2007). These devices are usually custom-fitted by a dentist and are more likely to be helpful in people who have mild-to-moderate sleep apnea, are younger, less overweight, and have a smaller neck circumference (Remmers 2013; Hoffstein 2007). Although less effective than CPAP, oral appliances are sometimes used in those who are unable to tolerate CPAP (Gutierrez 2013; Freedman 2014).

Medications

A rigorous literature review published in 2013 concluded that there was not adequate evidence to support the recommendation of any specific drug for the treatment of obstructive sleep apnea, though many trials have attempted to study medications for this purpose (Mason 2013). However, central sleep apnea may respond to medications that stimulate breathing or promote sedation. Evidence in support of pharmacological treatment of central sleep apnea is sparse. Modafinil (Provigil) has been approved for daytime sleepiness in patients with sleep apnea. Other medications that are sometimes prescribed, but are not FDA-approved for sleep apnea, include acetazolamide (Diamox) and theophylline, to stimulate breathing, as well as the sedatives temazepam (Restoril) and zolpidem (Ambien) (Becker 2014; Mayo Clinic 2013; Seda 2014; Eckert 2014; Dopp 2010; Launois 2013; Kielb 2012).

Some people with obstructive sleep apnea continue to suffer with excessive daytime sleepiness in spite of CPAP therapy or other treatments. Modafinil is a wakefulness-promoting medication that is effective in relieving daytime sleepiness in people with obstructive sleep apnea (Inoue 2013; Bittencourt 2008; Black 2005). Common side effects of modafinil include anxiety, headache, nausea, and nervousness (NLM 2015a).

Surgery

Surgery can be an important part of the treatment approach to sleep apnea when the obstruction is due to an obvious anatomical problem, such as enlarged tonsils or adenoids, or a deviated septum. There is considerable variability in the success rate of sleep apnea surgery, with estimates of benefit ranging from as low as 35% to as high as 92% (Li 2008; Camacho 2013; Kotecha 2014; Tien 2014; Khirani 2012). Surgical techniques can attempt to open the airway and decrease collapsibility. A combination of surgical methods may be recommended in some cases (Handler 2014; Tien 2014).

8 Novel and Emerging Strategies

Sex Hormones

Estrogen and progesterone. Interaction between sleep apnea and steroid hormones may partially explain the gender discrepancy in sleep apnea incidence. Female reproductive hormones appear to be protective against sleep apnea (Dursunoglu 2009; Tasali 2008). Postmenopausal women and women with polycystic ovary syndrome, two conditions marked by low estrogen and progesterone levels, are much more likely to have sleep apnea than healthy women in their reproductive years (Ehrmann 2012; Valipour 2012; Tamanna 2013). Also, women with sleep apnea have been found to have lower levels of estrogen and progesterone than women without sleep apnea (Netzer 2003).

Researchers have examined the role of estrogen and progesterone therapy in the treatment of sleep apnea in postmenopausal women. A large observational study found that postmenopausal women using hormone therapy were 50% less likely to have sleep apnea than women who did not use hormones (Shahar 2003). In one preliminary trial, after just one week of treatment with a combination of 1.25 mg of premarin (conjugated equine estrogens) and 20 mg of the progestin (synthetic progesterone-like compound) medroxyprogesterone acetate, a reduction in the number of apneic episodes was observed in nine surgically postmenopausal women (Pickett 1989). In another preliminary study, five postmenopausal women with sleep apnea experienced a 25% drop in apnea severity after taking 2 mg of micronized estradiol for 3–4 weeks, and a subsequent 50% reduction in severity from baseline when 10 mg of medroxyprogesterone acetate was added (Keefe 1999).

In another small preliminary trial, six postmenopausal women with mild-to-moderate sleep apnea used a transdermal estradiol patch providing 50 mg of estradiol per day for two weeks, and then added 200 mg per day of oral micronized progesterone for another two weeks. The women slept better and had fewer apneic and hypopneic episodes during treatment with estradiol, but the addition of progesterone produced no additional benefit (Manber 2003). In a preliminary trial involving five peri- or postmenopausal women with sleep apnea, a daily oral combination of 2 mg of estradiol plus 0.5 mg of the progestin trimegestone was associated with a mean 75% drop in sleep apnea severity (Wesstrom 2005).

Although the exact mechanism by which estrogen and progesterone might exert beneficial effects in sleep apnea is not entirely clear, studies sugest these hormones may play a role in maintaining muscular tone in the upper airway (Popovic 1998; Hou 2010; Liu 2009). Using bioidentical hormones, which are identical to the hormones produced naturally by the body, is the preferred method of hormone replacement.

More information about hormone replacement therapy for women is available in the Female Hormone Restoration protocol.

Testosterone. Sleep quality and testosterone levels are related, especially in older men, an effect largely explained by body fat content (adiposity). In men with obstructive sleep apnea, weight loss consistently restores testosterone levels, while the effect of CPAP on testosterone restoration is inconsistent (Barrett-Connor 2008; Wittert 2014; Zhang 2014; Bercea 2012; Knapp 2014). In addition, some researchers have noted that “Measuring testosterone level may be an additional helpful indicator in diagnosis of severity and in follow-up of [obstructive sleep apnea]” (Canguven 2010).

Testosterone therapy may have some positive impacts on cardiovascular and metabolic health in men with sleep apnea (Hoyos, Yee 2012), but some evidence shows a worsening of sleep apnea severity with testosterone therapy (Grech 2014; Andersen 2008; Hoyos, Killick 2012; Matsumoto 1985). However, one study found that the negative impact of testosterone therapy on sleep apnea resolved by week 18, suggesting a transient nature for this effect (Killick 2013). Nevertheless, current guidelines recommend against testosterone replacement therapy in men with untreated severe obstructive sleep apnea (Bhasin 2010). But some researchers have questioned this position, stating the evidence is weak and inconsistent (Hanafy 2007).

One possible approach is for men with low testosterone levels and untreated sleep apnea to receive treatment for their sleep apnea before initiating testosterone replacement therapy. These men should also lose weight if they are overweight. If low testosterone levels persist after successful sleep apnea treatment, then testosterone replacement therapy might be a reasonable consideration. Men who do initiate testosterone therapy after successful sleep apnea treatment should be closely monitored for reemergence of sleep apnea.

A more detailed discussion about testosterone replacement is included in the Male Hormone Restoration protocol.

Hypoglossal Nerve Stimulation

The hypoglossal nerve is one of the 12 cranial nerves (Gillig 2010). When stimulated, the hypoglossal nerve increases muscle tone in the tongue (Huang 2004; Gilliam 1995). Because increased tongue muscle tone may reduce airway obstruction, a hypoglossal nerve stimulating device has been developed for the treatment of sleep apnea. This device is surgically implanted on the chest wall and is connected to one or two chest leads, which measure breath cycles, and to a lead that delivers electrical stimulation to the hypoglossal nerve in the neck (Strollo 2014).

Several studies have looked at the effect of hypoglossal nerve stimulation in people with sleep apnea who were unsuccessful in using CPAP. In general, these have been uncontrolled trials lasting for 6 to 12 months in people with moderate-to-severe apnea. Use of these nerve-stimulating devices was associated with high degrees of safety and compliance, reductions of greater than 50% in apneic and hypopneic episodes, decreases in symptoms of sleep apnea, and improvements in quality of life measures (Eastwood 2011; Van de Heyning 2012; Strollo 2014; Mwenge 2013; Kezirian 2014). Although early data indicate a promise of benefit, hypoglossal nerve stimulators are still being studied and are approved only for investigational use in the United States as of early 2015 (Oliven 2011; Freedman 2014).

Renal Denervation

In sleep apnea, sleep is fragmented, which causes chronic overstimulation of the sympathetic nervous system; in other words, a prolonged stress response (Adeseun 2010; Canales 2008). One way the body responds to stress is by raising blood pressure to ensure sufficient blood flow to tissues like the heart, muscles, and brain. This occurs in large part by means of sympathetic nerve signaling via the renal nerves; this signal triggers vasoconstriction and sodium and fluid retention, resulting in increased blood pressure (Dusek 2009; Kannan 2014). Thus, it follows that one of the most prevalent and serious conditions correlated with sleep apnea is resistant hypertension, which is high blood pressure that persists despite aggressive drug treatment (Pedrosa 2011; Parati 2014; AHA 2014). Renal denervation, a technique in which renal sympathetic nerve fibers are selectively removed, is a new strategy being explored for the treatment of resistant hypertension as well as sleep apnea (Kannan 2014; Ukena 2013).

Renal denervation has been found, in preclinical and clinical models, to not only lower blood pressure but also improve severity of obstructive sleep apnea (Bohm 2013; Zhao 2013; Witkowski 2011). One study compared the effects of renal denervation to CPAP treatment in patients with moderate-to-severe obstructive sleep apnea as well as high blood pressure. Both treatments had a positive impact on sleep apnea and hypertension (Zhao 2013). A rigorous analysis of research into renal denervation for obstructive sleep apnea was published in 2014. This analysis examined data from five separate studies, involving a total of 49 people, all of whom were followed for six months after renal denervation. In these patients, renal denervation was associated with a significant decrease in severity of obstructive sleep apnea (Shantha 2014).

By reducing elevated sympathetic tone, thus interrupting the stress response, renal denervation may reduce severity of obstructive sleep apnea, and have broad benefits for cardiovascular health, glucose control, and weight management (Thomopoulos 2013). In fact, one study in 10 subjects with sleep apnea and treatment-resistant hypertension reported improved glucose control as well as reduced blood pressure and sleep apnea severity six months after renal denervation (Witkowski 2011).

However, as of early 2014 the only randomized controlled trial conducted on renal denervation for resistant hypertension found no benefit from the procedure, with only poor quality, unblinded studies showing a positive effect—though analysis of the data continues. Renal denervation may be associated with renal artery stenosis, which can actually raise blood pressure (Mahfoud 2013; Kwon 2014; Boyles 2014; Mandrola 2014).

Nasal Expiratory Positive Airway Pressure and Oral Negative Pressure Therapy

Because many people find CPAP difficult to use, other devices working on the same principle—using air pressure to keep airways open—have been developed.

Nasal expiratory positive airway pressure. This treatment creates positive pressure only in the expiratory phase of the breath cycle, rather than continuously. The pressure is generated by adhesive nasal patches that function as one-way valves that close during exhalation, providing air resistance pressure. These nasal patches may be more tolerable to some people than a CPAP facemask. Expiratory positive airway pressure reduces frequency and duration of apneas in people with obstructive sleep apnea, but works best in mild cases, and compares poorly to CPAP in severe obstructive sleep apnea. Expiratory positive airway pressure is contraindicated for people with nasal obstruction, obstructive lung disease, blood gas abnormalities, or severe obstructive sleep apnea (Freedman 2014; De Dios 2012).

Oral negative pressure therapy. In this therapy, negative pressure is provided through an oral suction device that draws the soft palate forward, maintaining airway patency. In a preliminary trial, oral negative pressure therapy significantly reduced obstructive sleep apnea severity, improved sleep quality, and decreased symptoms in a subgroup of participants. People who had positive effects from this treatment generally did so from the first night of use, and people with severe, moderate, and mild sleep apnea had equal chances of benefiting (Colrain 2013).

9 Dietary and Lifestyle Considerations

Weight Loss

Weight loss has been demonstrated to decrease the severity of obstructive sleep apnea, and has been called “the most important major modifiable risk factor associated with obstructive sleep apnea.” A study in 690 adults found that a 10% weight loss was predictive of a 26% drop in apnea-hypopnea index, while a 10% weight gain predicted a 32% increase in apnea-hypopnea index (Peppard 2000; Araghi 2013; Mitchell 2014; Bonsignore 2013). Also, it may be easier for people with obstructive sleep apnea to lose weight when dietary weight loss measures are accompanied by CPAP (Bonsignore 2013).

A six-month randomized study in 40 obese subjects with moderate-to-severe obstructive sleep apnea found that a low-calorie Mediterranean diet, combined with increased physical activity, was more effective for both weight loss and reduction in severity of sleep apnea than a low-calorie diet with a smaller increase in physical activity (Papandreou 2012). The Mediterranean diet emphasizes whole grains, legumes, fruits, vegetables, nuts, and fish (OPT 2015). Mediterranean eating patterns have also been shown to benefit people with diabetes, as well as help reduce risk of diabetes, high blood pressure, cardiovascular disease, and many other conditions (Salas-Salvado 2014; Esposito 2014; Domenech 2014; Toledo 2013; Estruch 2013; Ajala 2013; Khatri 2014; Filomeno 2014; Lourida 2013).

A thorough discussion of weight loss strategies is included in the Weight Loss protocol.

Exercise

Exercise, even without weight loss, appears to reduce severity and symptoms of obstructive sleep apnea (Iftikhar 2014). This was demonstrated in a study in 10 adult men and one adult woman who participated in a supervised exercise program of two hours twice weekly for six months. At enrollment, the participants already completed three months of CPAP, but the exercise program reduced a measure of respiratory disturbance (Giebelhaus 2000). Another study in subjects with obstructive sleep apnea found that a supervised exercise program involving 150 minutes per week of moderate intensity aerobic exercise plus strength training led to reductions in sleep apnea severity, depressive symptoms, and fatigue, and also improved daytime functioning (Kline 2012).

Acupuncture

Acupuncture may benefit individuals with obstructive sleep apnea, reducing the number of apneic and hypopneic events and improving oxygen levels (Bo 2008; Freire 2007; Freire 2010; Xu 2009). In one randomized, placebo-controlled study, 36 subjects with sleep apnea were divided into three treatment groups: acupuncture, sham acupuncture, and no treatment. After 10 weeks, subjects in the acupuncture group showed an improvement in the apnea-hypopnea index and a reduction in the number of respiratory events compared with the sham-acupuncture group. The no-treatment group exhibited an increase in the number of respiratory events during the study (Freire 2007). More well-designed studies are needed to firmly establish the role of acupuncture in the treatment of sleep apnea.

Preliminary studies also suggest that auricular therapies, in which acupuncture points on the external ear are stimulated, may be helpful for people with sleep apnea, but more research is needed in this area (Wang 2009; Wang 2003; Wu 2012).

Smoking Cessation

Smokers have a higher risk of developing obstructive sleep apnea, and at a younger age, than non-smokers. Also, people who smoke more cigarettes for a longer time are at greater risk for more severe sleep apnea. It is thought that smoking-related airway inflammation and loss of pharyngeal muscle tone due to nicotine withdrawal during sleep may contribute to increased risk among smokers (Lin 2012; Hizli 2013; Quan 2014; Boussoffara 2013).

Alcohol and Sedative Avoidance

Alcohol is a central nervous system depressant that can contribute to obstructive sleep apnea (Scanlan 2000; Juntunen 1984). Like other sedatives, it can decrease respiratory center activity and weaken the drive to inhale (Motamedi 2009; St John 1986; Stein 2005). It may also cause weakness in the muscular structures of the pharynx, increasing the tendency for airway collapse, causing snoring and obstructive apnea. People with sleep apnea have also been found to be more susceptible to the effects of alcohol and may have a higher risk of alcohol-related automobile accidents compared to people without sleep apnea (Vakulin 2009).

Sleep Position

For some people, sleep position has a marked impact on severity of apneic and hypopneic breathing during sleep. Lying on one’s back (supine position) has been linked to greater severity of sleep apnea, but studies show that certain people are more likely to benefit from a position change. Individuals with positional sleep apnea tend to be thinner and younger, have a smaller neck circumference, and have milder sleep apnea. In some cases, adjusting sleep position is all that is required to satisfactorily relieve obstructive sleep apnea (Menon 2013).

Strategies for maintaining a non-supine position during sleep include using barriers such as firm pillows or other props like tennis balls sewn into the back of a shirt to prevent rolling onto the back (Skinner 2008). However, many patients find these methods uncomfortable and stop using them (Oksenberg 2006; Bignold 2009; Park 2011).

Allergy and Asthma Management

People with allergies and asthma have a higher risk of obstructive sleep apnea. Airway resistance and nasal congestion may contribute to this relationship (Braido 2014; Koinis-Mitchell 2012). One study found that treatment of obstructive sleep apnea with CPAP eliminated nighttime asthma (Salles 2013).

Low Sodium Diet

High levels of aldosterone, an adrenal hormone that regulates the concentration of sodium and potassium in the body, have been noted in people with sleep apnea and treatment-resistant hypertension (Calhoun 2004; Grossman 2014). One research group found that in people with obstructive sleep apnea who also have hypertension and hyperaldosteronism, urinary sodium level independently predicted severity of sleep apnea (Pimenta 2013). A similar study found that higher morning urinary sodium was linked to more severe obstructive sleep disordered breathing in children (Kaditis 2010). Since urinary sodium is generally a reflection of dietary sodium intake, and dietary sodium is related to obstructive sleep apnea severity in patients with resistant hypertension and hyperaldosteronism, dietary sodium restriction has been proposed as a treatment strategy for reduction of obstructive sleep apnea severity in such patients (Pimenta 2013; Grimes 2013; Cirillo 1997).

10 Integrative Interventions

In addition to the interventions described in this protocol, readers should also review the Life Extension protocols on Weight Loss, Cardiovascular Disease, Chronic Inflammation, and Diabetes, given the strong associations between sleep apnea and metabolic health. In addition, a number of strategies for improving sleep quality and sleep hygiene in general are described in the Insomnia protocol and may be of use for those with sleep apnea.

N-Acetyl Cysteine

Cysteine is an amino acid used by the body to synthesize the critical detoxification and antioxidant molecule glutathione; and N-acetyl cysteine (NAC) has mucus-reducing (mucolytic) properties (Tse 2014; Lu 2013). In a placebo-controlled, randomized trial in 20 adults with obstructive sleep apnea, 600 mg of NAC was given three times daily for 30 days. The NAC group experienced multiple significant improvements in measurements of apnea severity and sleep quality. NAC produced marked reductions in snoring and sleepiness compared with placebo. The NAC group showed significant reductions in oxidative stress as measured by lipid peroxidation and total reduced glutathione level (Sadasivam 2011). In an animal model of sleep apnea, supplementation with NAC mitigated oxidative stress and inflammation that occurred as a result of intermittent hypoxia (da Rosa 2015). 

Vitamin C

In a preliminary study, 10 people with obstructive sleep apnea were found to have dysfunction of the delicate lining of blood vessels (the endothelium) compared with 10 healthy controls. After a single 500 mg dose of intravenous vitamin C, endothelial function improved to a level comparable to that of the healthy subjects (Grebe 2006). In another study, a combination of 100 mg of vitamin C and 400 IU of vitamin E, taken by mouth twice daily for 45 days, led to reductions in apneic episodes and daytime sleepiness, and improved sleep quality, in obstructive sleep apnea patients being treated with CPAP. People taking the vitamin C and E combination were able to reduce pressure settings on their CPAP machines (Singh 2009).

Vitamin E

Individuals with obstructive sleep apnea have been reported to have low vitamin E levels (Barcelo 2006). As mentioned previously, combination vitamin E and C treatment was shown to benefit patients with obstructive sleep apnea (Singh 2009). Another study used a combination antioxidant treatment that included vitamin E in a comparison of breathing function in 13 healthy men and 13 men with obstructive sleep apnea. Both groups were exposed to intermittent hypoxia to mimic sleep apnea conditions, but before this exposure participants were randomly selected to receive pretreatment with either an antioxidant cocktail or placebo. The antioxidant treatment was an oral combination of 200 IU vitamin E, 60 mg coenzyme Q10, and 400 mg of the enzyme superoxide dismutase, given with yogurt, along with two intravenous doses of 1000 mg vitamin C. In the placebo group, both healthy controls and those with sleep apnea showed increased involuntary breathing effort, though that effort was significantly greater in the sleep apnea group. However, the men with obstructive sleep apnea who received the antioxidant treatment showed significantly better respiratory function compared with those receiving placebo treatment (Lee 2009).

Coenzyme Q10

Coenzyme Q10 (CoQ10) is involved in mitochondrial energy production and is best known for its beneficial effects on the heart and cardiovascular system (Garrido-Maraver 2014). As demonstrated in the study mentioned previously, CoQ10 in combination with other antioxidants favorably influenced respiratory function in men with obstructive sleep apnea (Lee 2009). It should be noted that patients with sleep apnea are at increased risk for cardiovascular disease, high blood pressure, and impaired glucose tolerance; and supplementation with CoQ10 may confer a benefit in all of these conditions (Kizaki 2014; Amin 2014; Garrido-Maraver 2014; Schmelzer 2008).

Selenium

Selenium is an essential component and regulator of an enzyme called glutathione peroxidase, which is an important part of the body’s cellular oxidative stress defense systems (Rotruck 1973; Baker 1993). In a study of trace minerals in 44 individuals newly diagnosed with mild-to-moderate obstructive sleep apnea compared to 20 healthy controls, those with sleep apnea had lower levels of red blood cell selenium and glutathione peroxidase activity than people without apnea. There were significant differences in these measures between those with moderate compared to mild obstructive sleep apnea. The apnea-hypopnea index, the standard measurement of apnea and hypopnea severity, was higher in patients with lower red blood cell selenium (Chen 2013). One researcher reported on the case of his 70-year old wife whose mild obstructive sleep apnea was subjectively improved after taking 100 mcg of L-selenomethionine per day (Dekok 2005).

Vitamin D

Low vitamin D status has been linked to a wide array of common chronic conditions including heart disease, obesity, diabetes, autoimmune diseases, and some cancers (Grineva 2013; Basit 2013; Foss 2009); low vitamin D levels may also be associated with sleep apnea.

A study with 150 participants found vitamin D deficiency to be more pronounced in people with severe sleep apnea compared to those with mild-to-moderate sleep apnea (Mete 2013). This finding was corroborated in another study, in which the authors suggested that vitamin D supplementation be considered in obstructive sleep apnea patients for its role in normalizing glucose metabolism and inflammation (Bozkurt 2012).

As vitamin D level increases, parathyroid hormone level tends to decrease (Muscogiuri 2014). A study in 128 people found that vitamin D levels were lower and parathyroid hormone levels were higher in people with obstructive sleep apnea than in a control group without the condition (Erden 2014). In another study in 826 people with obstructive sleep apnea, those with insufficient vitamin D status were more likely to have diabetes and metabolic syndrome, and those with higher levels of parathyroid hormone were more likely to have hypertension and obesity (Barcelo 2013).

Maintaining healthy vitamin D status may also protect against a host of other chronic diseases, both related and unrelated to sleep apnea (Basit 2013; Muscogiuri 2014).  

Omega-3 Fatty Acids

Sufficient levels of the polyunsaturated omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been linked to lower degrees of systemic inflammation and lower risk of many chronic diseases, including those correlated with sleep apnea (Scorza 2013). A study that examined the red blood cell membrane fatty acid profiles of individuals with obstructive sleep apnea found that lower membrane DHA levels were associated with increased likelihood of severe sleep apnea. The authors suggest that red blood cell DHA testing could play a role in the diagnosis of obstructive sleep apnea, and further studies should investigate the effects of DHA supplementation in obstructive sleep apnea (Ladesich 2011).

B Vitamins

A number of studies have found that people with obstructive sleep apnea have higher levels of homocysteine, an amino acid linked to increased risk of cardiovascular and neurodegenerative diseases (Niu 2014; Monneret 2012; Sariman 2010; Ansari 2014; Jordan 2004).

High homocysteine levels may be more common in people with sleep apnea who also have hypertension, ischemic heart disease, or obesity; in those diagnosed with sleep apnea before age 50; and in those with more severe sleep apnea (Lavie 2001; Niu 2014). A rigorous analysis of six studies in a total of 206 participants concluded that CPAP could effectively lower high homocysteine levels in people with obstructive sleep apnea when they used the device for three months or more (Chen, Niu 2014).

Supplementation with the B vitamins folate, B6, and B12 can reduce serum homocysteine levels (Smach 2013) and may be effective in cardiovascular disease prevention (Debreceni 2014). Because of the close relationship between sleep apnea and heart disease, B vitamin supplementation may be important in people with sleep apnea. Importantly, evidence suggests supplementation with methylfolate, a metabolically active form of folate, may outperform folic acid supplementation for homocysteine reduction (Akoglu 2008; Venn 2003; Litynski 2002).

More information about the importance of keeping homocysteine levels low and strategies to do so are available in the Homocysteine Reduction protocol.

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