Sleep Medicine

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

The odds of adulthood insomnia are significantly higher among those with childhood behavioral problems, according to research published in JAMA Network Open.

klebercordeiro/Getty Images

Yohannes Adama Melaku, MPH, PhD, of the Adelaide (Australia) Institute for Sleep Health at Flinders University and coauthors drew data from the 1970 UK Birth Cohort Study. This study followed an initial cohort of 16,571 babies who were born during a single week, with follow-up at ages 5, 10, 16, 26, 30, 38, 42, and 46 years. For the purposes of this study, the investigators looked at participants who, at 42 years of age, were alive and not lost to follow-up and who responded to an invitation to be interviewed; the sample sizes in the analysis were 8,050 participants aged 5 years, 9,090 participants aged 10 years, 9,653 participants aged 16 years, and 9,841 participants aged 42 years.

Behavior was measured at ages 5 years and 16 years using the Rutter Behavioral Scale (RBS) and at age 10 years using a visual analog scale, and insomnia symptoms were assessed through interviewing participants in adulthood about duration of sleep, difficulty initiating sleep, difficulty maintaining sleep, and not feeling rested on waking. Participants were organized into normal behavior (less than or equal to 80th percentile on RBS), moderate behavioral problems (greater than the 80th percentile but less than or equal to the 95th percentile), and severe behavioral problems (above 95th percentile). The investigators then devised two models for their analysis: Model 1 adjusted for sex, parent’s social class and educational level, marital status, educational status, and social class, and model 2 adjusted for physical activity level and body mass index (BMI) trajectory (from 10 to 42 years), perceived health status, and number of noncommunicable diseases, although this latter model yielded fewer statistically significant results in some analyses.

Odds for difficulty initiating or maintaining sleep as an adult was increased among participants with severe behavioral problems at age 5 years in model 1 (adjusted odds ratio, 1.50; 95% confidence interval, 1.14-1.96; P = .004), as well as for those with severe problems at 10 years (aOR, 1.30; 95% CI, 1.14-1.63; P = .001), and at 16 years (aOR, 2.17; 95% CI, 1.59-2.91; P less than .001). The aORs also were higher individually for difficulty initiating sleep and for difficulty maintaining sleep in all age groups.

The association with adulthood insomnia was stronger in participants with externalizing behavioral problems such as lying, bullying, restlessness, and fighting than it was in those with internalizing behavioral problems such as worry, fearfulness, and solitariness.

“Although early sleep problems should be identified, we should additionally identify children with moderate to severe behavioral problems that persist throughout childhood as potential beneficiaries of early intervention with a sleep health focus,” the authors wrote.

One of the study’s limitations was a lack of standardized insomnia measures in the cohort study; however, the researchers suggested that the symptoms included reflect those of standardized measures and diagnostic criteria.

“This study is the first, to our knowledge, to suggest an unfavorable association of early-life behavioral problems with adulthood sleep health, underlining the importance of treating behavioral problems in children and addressing insomnia from a life-course perspective,” they concluded.

No study sponsor was identified. The authors reported no relevant financial disclosures.
 

[email protected]

SOURCE: Melaku YA et al. JAMA Netw Open. 2019 Sep 6. doi: 10.1001/jamanetworkopen.2019.10861.

The odds of adulthood insomnia are significantly higher among those with childhood behavioral problems, according to research published in JAMA Network Open.

klebercordeiro/Getty Images

Yohannes Adama Melaku, MPH, PhD, of the Adelaide (Australia) Institute for Sleep Health at Flinders University and coauthors drew data from the 1970 UK Birth Cohort Study. This study followed an initial cohort of 16,571 babies who were born during a single week, with follow-up at ages 5, 10, 16, 26, 30, 38, 42, and 46 years. For the purposes of this study, the investigators looked at participants who, at 42 years of age, were alive and not lost to follow-up and who responded to an invitation to be interviewed; the sample sizes in the analysis were 8,050 participants aged 5 years, 9,090 participants aged 10 years, 9,653 participants aged 16 years, and 9,841 participants aged 42 years.

Behavior was measured at ages 5 years and 16 years using the Rutter Behavioral Scale (RBS) and at age 10 years using a visual analog scale, and insomnia symptoms were assessed through interviewing participants in adulthood about duration of sleep, difficulty initiating sleep, difficulty maintaining sleep, and not feeling rested on waking. Participants were organized into normal behavior (less than or equal to 80th percentile on RBS), moderate behavioral problems (greater than the 80th percentile but less than or equal to the 95th percentile), and severe behavioral problems (above 95th percentile). The investigators then devised two models for their analysis: Model 1 adjusted for sex, parent’s social class and educational level, marital status, educational status, and social class, and model 2 adjusted for physical activity level and body mass index (BMI) trajectory (from 10 to 42 years), perceived health status, and number of noncommunicable diseases, although this latter model yielded fewer statistically significant results in some analyses.

Odds for difficulty initiating or maintaining sleep as an adult was increased among participants with severe behavioral problems at age 5 years in model 1 (adjusted odds ratio, 1.50; 95% confidence interval, 1.14-1.96; P = .004), as well as for those with severe problems at 10 years (aOR, 1.30; 95% CI, 1.14-1.63; P = .001), and at 16 years (aOR, 2.17; 95% CI, 1.59-2.91; P less than .001). The aORs also were higher individually for difficulty initiating sleep and for difficulty maintaining sleep in all age groups.

The association with adulthood insomnia was stronger in participants with externalizing behavioral problems such as lying, bullying, restlessness, and fighting than it was in those with internalizing behavioral problems such as worry, fearfulness, and solitariness.

“Although early sleep problems should be identified, we should additionally identify children with moderate to severe behavioral problems that persist throughout childhood as potential beneficiaries of early intervention with a sleep health focus,” the authors wrote.

One of the study’s limitations was a lack of standardized insomnia measures in the cohort study; however, the researchers suggested that the symptoms included reflect those of standardized measures and diagnostic criteria.

“This study is the first, to our knowledge, to suggest an unfavorable association of early-life behavioral problems with adulthood sleep health, underlining the importance of treating behavioral problems in children and addressing insomnia from a life-course perspective,” they concluded.

No study sponsor was identified. The authors reported no relevant financial disclosures.
 

[email protected]

SOURCE: Melaku YA et al. JAMA Netw Open. 2019 Sep 6. doi: 10.1001/jamanetworkopen.2019.10861.

The odds of adulthood insomnia are significantly higher among those with childhood behavioral problems, according to research published in JAMA Network Open.

klebercordeiro/Getty Images

Yohannes Adama Melaku, MPH, PhD, of the Adelaide (Australia) Institute for Sleep Health at Flinders University and coauthors drew data from the 1970 UK Birth Cohort Study. This study followed an initial cohort of 16,571 babies who were born during a single week, with follow-up at ages 5, 10, 16, 26, 30, 38, 42, and 46 years. For the purposes of this study, the investigators looked at participants who, at 42 years of age, were alive and not lost to follow-up and who responded to an invitation to be interviewed; the sample sizes in the analysis were 8,050 participants aged 5 years, 9,090 participants aged 10 years, 9,653 participants aged 16 years, and 9,841 participants aged 42 years.

Behavior was measured at ages 5 years and 16 years using the Rutter Behavioral Scale (RBS) and at age 10 years using a visual analog scale, and insomnia symptoms were assessed through interviewing participants in adulthood about duration of sleep, difficulty initiating sleep, difficulty maintaining sleep, and not feeling rested on waking. Participants were organized into normal behavior (less than or equal to 80th percentile on RBS), moderate behavioral problems (greater than the 80th percentile but less than or equal to the 95th percentile), and severe behavioral problems (above 95th percentile). The investigators then devised two models for their analysis: Model 1 adjusted for sex, parent’s social class and educational level, marital status, educational status, and social class, and model 2 adjusted for physical activity level and body mass index (BMI) trajectory (from 10 to 42 years), perceived health status, and number of noncommunicable diseases, although this latter model yielded fewer statistically significant results in some analyses.

Odds for difficulty initiating or maintaining sleep as an adult was increased among participants with severe behavioral problems at age 5 years in model 1 (adjusted odds ratio, 1.50; 95% confidence interval, 1.14-1.96; P = .004), as well as for those with severe problems at 10 years (aOR, 1.30; 95% CI, 1.14-1.63; P = .001), and at 16 years (aOR, 2.17; 95% CI, 1.59-2.91; P less than .001). The aORs also were higher individually for difficulty initiating sleep and for difficulty maintaining sleep in all age groups.

The association with adulthood insomnia was stronger in participants with externalizing behavioral problems such as lying, bullying, restlessness, and fighting than it was in those with internalizing behavioral problems such as worry, fearfulness, and solitariness.

“Although early sleep problems should be identified, we should additionally identify children with moderate to severe behavioral problems that persist throughout childhood as potential beneficiaries of early intervention with a sleep health focus,” the authors wrote.

One of the study’s limitations was a lack of standardized insomnia measures in the cohort study; however, the researchers suggested that the symptoms included reflect those of standardized measures and diagnostic criteria.

“This study is the first, to our knowledge, to suggest an unfavorable association of early-life behavioral problems with adulthood sleep health, underlining the importance of treating behavioral problems in children and addressing insomnia from a life-course perspective,” they concluded.

No study sponsor was identified. The authors reported no relevant financial disclosures.
 

[email protected]

SOURCE: Melaku YA et al. JAMA Netw Open. 2019 Sep 6. doi: 10.1001/jamanetworkopen.2019.10861.

A new study found no association between sleep position during pregnancy and risk of adverse pregnancy outcomes such as stillbirth, small-for-gestational-age (SGA) newborns, and gestational hypertensive disorders. The finding, published in the October issue of Obstetrics & Gynecology, conflicts with previous retrospective case-control studies that suggested left-side sleeping may lead to reduced risk. The disagreement may be due to the prospective nature of the new study, which followed 8,706 women over 4 years.

©Brand X Pictures/thinkstockphotos.com

Right-side or back sleeping had attracted suspicion because of its potential to compress uterine blood vessels and decrease uterine blood flow, and various public health campaigns urge pregnant women to sleep on their left side. Although case-control studies backed up those worries, those retrospective approaches can suffer from limitations including recall bias, in which grieving mothers overreport suspect sleeping behaviors, perhaps in search of an explanation for their loss.

Prospective analyses can counter some of those limitations. The researchers, led by Robert Silver, MD, of the University of Utah, Salt Lake City, conducted a secondary analysis of the nuMoM2b study, examining adverse pregnancy outcomes and risk factors. It was a multicenter observational cohort study of 8,706 nulliparous women with singleton gestations who completed two sleep questionnaires: one between 6 and 13 weeks of gestation, and one between 22 and 29 weeks.

Adverse outcomes occurred in 1,903 women, including 178 cases of both SGA and hypertensive disorders, 8 with SGA plus stillbirth, 3 with hypertensive disorders plus stillbirth, and 2 cases with all three complications.

The researchers found no association between any adverse outcomes and sleep position either at the first visit in early pregnancy (adjusted odds ratio, 1.00; 95% confidence interval, 0.89-1.14) or the third visit in midpregnancy (aOR, 0.99; 95% CI, 0.89-1.11). Propensity score matching to adjust non-left lateral positioning to the composite outcome also showed no association.

In midpregnancy, there was an association between non-left lateral sleeping and reduced risk of stillbirth (aOR, 0.27; 95% CI, 0.09-0.75). “This observation is likely spurious owing to small numbers of stillbirths, Dr. Silver and associates said.

A post hoc analysis indicated that the study was sufficiently powered to detect clinically meaningful risks; ORs of 1.2 for hypertensive disorders, 1.23 for SGA, 2.4 for stillbirth, and 1.2 for the composite outcome.
 

Let sleeping mothers lie

Pregnant women have enough on their minds. They shouldn’t have to worry about sleep position as well, according to Nathan Fox, MD, professor of obstetrics, gynecology, and reproductive science at Icahn School of Medicine at Mount Sinai, New York, and Emily Oster, PhD, economist at Brown University, Providence, R.I., who wrote an accompanying editorial.

It may seem harmless to direct women to sleep on their left side even if it has no benefit, but restricting a woman’s sleep options may leave her less well rested at a time when she is about to enter a period of sleep deprivation, as well as contribute to general discomfort, in their opinion.

Also, in the rare cases of a bad outcome, advice based on limited or poor quality evidence contributes to “devastating and unwarranted feelings of responsibility and guilt, and this harm to women already suffering from sadness and despair must not be minimized,” they said.

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants from multiple universities. One author received research funding from Kyndermed through her institution. Another receives royalties from UpToDate.com. Dr. Fox and Dr. Oster have no relevant financial disclosures.

SOURCES: Silver RM et al. Obstet Gynecol. 2019. doi: 10.1097/AOG.0000000000003458; Fox N and Oster E. Obstet. Gynecol. 2019 Oct. doi: 10.1097/AOG.0000000000003466

A new study found no association between sleep position during pregnancy and risk of adverse pregnancy outcomes such as stillbirth, small-for-gestational-age (SGA) newborns, and gestational hypertensive disorders. The finding, published in the October issue of Obstetrics & Gynecology, conflicts with previous retrospective case-control studies that suggested left-side sleeping may lead to reduced risk. The disagreement may be due to the prospective nature of the new study, which followed 8,706 women over 4 years.

©Brand X Pictures/thinkstockphotos.com

Right-side or back sleeping had attracted suspicion because of its potential to compress uterine blood vessels and decrease uterine blood flow, and various public health campaigns urge pregnant women to sleep on their left side. Although case-control studies backed up those worries, those retrospective approaches can suffer from limitations including recall bias, in which grieving mothers overreport suspect sleeping behaviors, perhaps in search of an explanation for their loss.

Prospective analyses can counter some of those limitations. The researchers, led by Robert Silver, MD, of the University of Utah, Salt Lake City, conducted a secondary analysis of the nuMoM2b study, examining adverse pregnancy outcomes and risk factors. It was a multicenter observational cohort study of 8,706 nulliparous women with singleton gestations who completed two sleep questionnaires: one between 6 and 13 weeks of gestation, and one between 22 and 29 weeks.

Adverse outcomes occurred in 1,903 women, including 178 cases of both SGA and hypertensive disorders, 8 with SGA plus stillbirth, 3 with hypertensive disorders plus stillbirth, and 2 cases with all three complications.

The researchers found no association between any adverse outcomes and sleep position either at the first visit in early pregnancy (adjusted odds ratio, 1.00; 95% confidence interval, 0.89-1.14) or the third visit in midpregnancy (aOR, 0.99; 95% CI, 0.89-1.11). Propensity score matching to adjust non-left lateral positioning to the composite outcome also showed no association.

In midpregnancy, there was an association between non-left lateral sleeping and reduced risk of stillbirth (aOR, 0.27; 95% CI, 0.09-0.75). “This observation is likely spurious owing to small numbers of stillbirths, Dr. Silver and associates said.

A post hoc analysis indicated that the study was sufficiently powered to detect clinically meaningful risks; ORs of 1.2 for hypertensive disorders, 1.23 for SGA, 2.4 for stillbirth, and 1.2 for the composite outcome.
 

Let sleeping mothers lie

Pregnant women have enough on their minds. They shouldn’t have to worry about sleep position as well, according to Nathan Fox, MD, professor of obstetrics, gynecology, and reproductive science at Icahn School of Medicine at Mount Sinai, New York, and Emily Oster, PhD, economist at Brown University, Providence, R.I., who wrote an accompanying editorial.

It may seem harmless to direct women to sleep on their left side even if it has no benefit, but restricting a woman’s sleep options may leave her less well rested at a time when she is about to enter a period of sleep deprivation, as well as contribute to general discomfort, in their opinion.

Also, in the rare cases of a bad outcome, advice based on limited or poor quality evidence contributes to “devastating and unwarranted feelings of responsibility and guilt, and this harm to women already suffering from sadness and despair must not be minimized,” they said.

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants from multiple universities. One author received research funding from Kyndermed through her institution. Another receives royalties from UpToDate.com. Dr. Fox and Dr. Oster have no relevant financial disclosures.

SOURCES: Silver RM et al. Obstet Gynecol. 2019. doi: 10.1097/AOG.0000000000003458; Fox N and Oster E. Obstet. Gynecol. 2019 Oct. doi: 10.1097/AOG.0000000000003466

A new study found no association between sleep position during pregnancy and risk of adverse pregnancy outcomes such as stillbirth, small-for-gestational-age (SGA) newborns, and gestational hypertensive disorders. The finding, published in the October issue of Obstetrics & Gynecology, conflicts with previous retrospective case-control studies that suggested left-side sleeping may lead to reduced risk. The disagreement may be due to the prospective nature of the new study, which followed 8,706 women over 4 years.

©Brand X Pictures/thinkstockphotos.com

Right-side or back sleeping had attracted suspicion because of its potential to compress uterine blood vessels and decrease uterine blood flow, and various public health campaigns urge pregnant women to sleep on their left side. Although case-control studies backed up those worries, those retrospective approaches can suffer from limitations including recall bias, in which grieving mothers overreport suspect sleeping behaviors, perhaps in search of an explanation for their loss.

Prospective analyses can counter some of those limitations. The researchers, led by Robert Silver, MD, of the University of Utah, Salt Lake City, conducted a secondary analysis of the nuMoM2b study, examining adverse pregnancy outcomes and risk factors. It was a multicenter observational cohort study of 8,706 nulliparous women with singleton gestations who completed two sleep questionnaires: one between 6 and 13 weeks of gestation, and one between 22 and 29 weeks.

Adverse outcomes occurred in 1,903 women, including 178 cases of both SGA and hypertensive disorders, 8 with SGA plus stillbirth, 3 with hypertensive disorders plus stillbirth, and 2 cases with all three complications.

The researchers found no association between any adverse outcomes and sleep position either at the first visit in early pregnancy (adjusted odds ratio, 1.00; 95% confidence interval, 0.89-1.14) or the third visit in midpregnancy (aOR, 0.99; 95% CI, 0.89-1.11). Propensity score matching to adjust non-left lateral positioning to the composite outcome also showed no association.

In midpregnancy, there was an association between non-left lateral sleeping and reduced risk of stillbirth (aOR, 0.27; 95% CI, 0.09-0.75). “This observation is likely spurious owing to small numbers of stillbirths, Dr. Silver and associates said.

A post hoc analysis indicated that the study was sufficiently powered to detect clinically meaningful risks; ORs of 1.2 for hypertensive disorders, 1.23 for SGA, 2.4 for stillbirth, and 1.2 for the composite outcome.
 

Let sleeping mothers lie

Pregnant women have enough on their minds. They shouldn’t have to worry about sleep position as well, according to Nathan Fox, MD, professor of obstetrics, gynecology, and reproductive science at Icahn School of Medicine at Mount Sinai, New York, and Emily Oster, PhD, economist at Brown University, Providence, R.I., who wrote an accompanying editorial.

It may seem harmless to direct women to sleep on their left side even if it has no benefit, but restricting a woman’s sleep options may leave her less well rested at a time when she is about to enter a period of sleep deprivation, as well as contribute to general discomfort, in their opinion.

Also, in the rare cases of a bad outcome, advice based on limited or poor quality evidence contributes to “devastating and unwarranted feelings of responsibility and guilt, and this harm to women already suffering from sadness and despair must not be minimized,” they said.

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants from multiple universities. One author received research funding from Kyndermed through her institution. Another receives royalties from UpToDate.com. Dr. Fox and Dr. Oster have no relevant financial disclosures.

SOURCES: Silver RM et al. Obstet Gynecol. 2019. doi: 10.1097/AOG.0000000000003458; Fox N and Oster E. Obstet. Gynecol. 2019 Oct. doi: 10.1097/AOG.0000000000003466

Among patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), lung function and continuous positive airway pressure (CPAP) use are independent predictors of COPD exacerbations and all‐cause mortality, according to a retrospective cohort study.

“These factors should be taken into account when considering the management and prognosis of these patients,” the researchers said in the Clinical Respiratory Journal.

Prior studies have found that patients with COPD and OSA – that is, with overlap syndrome – “have a substantially greater risk of morbidity and mortality, compared to those with either COPD or OSA alone,” said Philippe E. Jaoude, MD, and Ali A. El Solh, MD, both of the Veterans Affairs Western New York Healthcare System in Buffalo and the University at Buffalo.

To identify factors associated with COPD exacerbation and all‐cause mortality in patients with overlap syndrome, Dr. Jaoude and Dr. El Solh reviewed the electronic health records of patients with simultaneous COPD and OSA. They compared patients with overlap syndrome who had an acute exacerbation of COPD during a 42-month period with a control group of patients with overlap syndrome who did not have exacerbations during that time. Patients with exacerbations and controls were matched 1:1 by age and body mass index.

Eligible patients were aged 42-90 years, had objectively confirmed COPD, and had documented OSA by in-laboratory polysomnography (that is, at least five obstructive apneas and hypopneas per hour). The investigators defined a COPD exacerbation as a sustained worsening of a patient’s respiratory condition that warranted additional treatment.

Of 225 eligible patients, 92 had at least one COPD exacerbation between March 2014 and September 2017. Patients with COPD exacerbation and controls had a mean age of about 68 years. The group of patients with exacerbation had a higher percentage of active smokers (21% vs. 9%) and had poorer lung function (mean forced expiratory volume in 1 second percent predicted: 55.2% vs. 64.5%).

“Although the rate of CPAP adherence between the two groups was not significantly different, the average time of CPAP use was significantly higher in patients with no recorded exacerbation,” the researchers reported – 285.4 min/night versus 238.2 min/night.

In all, 146 patients (79.4%) survived, and 38 patients (20.6%) died during the study period. The crude mortality rate was significantly higher in the group with COPD exacerbations (14% vs. 7%).

“Multivariate logistic regression analysis identified the independent risk factors associated with COPD exacerbations as active smoking, worse airflow limitation, and lower CPAP utilization,” they said. “As for all-cause mortality, a higher burden of comorbidities, worse airflow limitation, and lower time of CPAP use were independently associated with poor outcome.”

The researchers noted that they cannot rule out the possibility that patients who were adherent to CPAP were systematically different from those who were not.

The authors had no conflicts of interest.

[email protected]

SOURCE: Jaoude P et al. Clin Respir J. 2019 Aug 22. doi: 10.1111/crj.13079.

Among patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), lung function and continuous positive airway pressure (CPAP) use are independent predictors of COPD exacerbations and all‐cause mortality, according to a retrospective cohort study.

“These factors should be taken into account when considering the management and prognosis of these patients,” the researchers said in the Clinical Respiratory Journal.

Prior studies have found that patients with COPD and OSA – that is, with overlap syndrome – “have a substantially greater risk of morbidity and mortality, compared to those with either COPD or OSA alone,” said Philippe E. Jaoude, MD, and Ali A. El Solh, MD, both of the Veterans Affairs Western New York Healthcare System in Buffalo and the University at Buffalo.

To identify factors associated with COPD exacerbation and all‐cause mortality in patients with overlap syndrome, Dr. Jaoude and Dr. El Solh reviewed the electronic health records of patients with simultaneous COPD and OSA. They compared patients with overlap syndrome who had an acute exacerbation of COPD during a 42-month period with a control group of patients with overlap syndrome who did not have exacerbations during that time. Patients with exacerbations and controls were matched 1:1 by age and body mass index.

Eligible patients were aged 42-90 years, had objectively confirmed COPD, and had documented OSA by in-laboratory polysomnography (that is, at least five obstructive apneas and hypopneas per hour). The investigators defined a COPD exacerbation as a sustained worsening of a patient’s respiratory condition that warranted additional treatment.

Of 225 eligible patients, 92 had at least one COPD exacerbation between March 2014 and September 2017. Patients with COPD exacerbation and controls had a mean age of about 68 years. The group of patients with exacerbation had a higher percentage of active smokers (21% vs. 9%) and had poorer lung function (mean forced expiratory volume in 1 second percent predicted: 55.2% vs. 64.5%).

“Although the rate of CPAP adherence between the two groups was not significantly different, the average time of CPAP use was significantly higher in patients with no recorded exacerbation,” the researchers reported – 285.4 min/night versus 238.2 min/night.

In all, 146 patients (79.4%) survived, and 38 patients (20.6%) died during the study period. The crude mortality rate was significantly higher in the group with COPD exacerbations (14% vs. 7%).

“Multivariate logistic regression analysis identified the independent risk factors associated with COPD exacerbations as active smoking, worse airflow limitation, and lower CPAP utilization,” they said. “As for all-cause mortality, a higher burden of comorbidities, worse airflow limitation, and lower time of CPAP use were independently associated with poor outcome.”

The researchers noted that they cannot rule out the possibility that patients who were adherent to CPAP were systematically different from those who were not.

The authors had no conflicts of interest.

[email protected]

SOURCE: Jaoude P et al. Clin Respir J. 2019 Aug 22. doi: 10.1111/crj.13079.

Among patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), lung function and continuous positive airway pressure (CPAP) use are independent predictors of COPD exacerbations and all‐cause mortality, according to a retrospective cohort study.

“These factors should be taken into account when considering the management and prognosis of these patients,” the researchers said in the Clinical Respiratory Journal.

Prior studies have found that patients with COPD and OSA – that is, with overlap syndrome – “have a substantially greater risk of morbidity and mortality, compared to those with either COPD or OSA alone,” said Philippe E. Jaoude, MD, and Ali A. El Solh, MD, both of the Veterans Affairs Western New York Healthcare System in Buffalo and the University at Buffalo.

To identify factors associated with COPD exacerbation and all‐cause mortality in patients with overlap syndrome, Dr. Jaoude and Dr. El Solh reviewed the electronic health records of patients with simultaneous COPD and OSA. They compared patients with overlap syndrome who had an acute exacerbation of COPD during a 42-month period with a control group of patients with overlap syndrome who did not have exacerbations during that time. Patients with exacerbations and controls were matched 1:1 by age and body mass index.

Eligible patients were aged 42-90 years, had objectively confirmed COPD, and had documented OSA by in-laboratory polysomnography (that is, at least five obstructive apneas and hypopneas per hour). The investigators defined a COPD exacerbation as a sustained worsening of a patient’s respiratory condition that warranted additional treatment.

Of 225 eligible patients, 92 had at least one COPD exacerbation between March 2014 and September 2017. Patients with COPD exacerbation and controls had a mean age of about 68 years. The group of patients with exacerbation had a higher percentage of active smokers (21% vs. 9%) and had poorer lung function (mean forced expiratory volume in 1 second percent predicted: 55.2% vs. 64.5%).

“Although the rate of CPAP adherence between the two groups was not significantly different, the average time of CPAP use was significantly higher in patients with no recorded exacerbation,” the researchers reported – 285.4 min/night versus 238.2 min/night.

In all, 146 patients (79.4%) survived, and 38 patients (20.6%) died during the study period. The crude mortality rate was significantly higher in the group with COPD exacerbations (14% vs. 7%).

“Multivariate logistic regression analysis identified the independent risk factors associated with COPD exacerbations as active smoking, worse airflow limitation, and lower CPAP utilization,” they said. “As for all-cause mortality, a higher burden of comorbidities, worse airflow limitation, and lower time of CPAP use were independently associated with poor outcome.”

The researchers noted that they cannot rule out the possibility that patients who were adherent to CPAP were systematically different from those who were not.

The authors had no conflicts of interest.

[email protected]

SOURCE: Jaoude P et al. Clin Respir J. 2019 Aug 22. doi: 10.1111/crj.13079.

A blood test for elevated carbon dioxide may be used in screening adults for obesity hypoventilation syndrome, according to new guidelines.

Obese adults with sleep-disordered breathing and increased blood carbon dioxide levels during the day are likely to have obesity hypoventilation syndrome (OHS), a result of shallow or slow breathing that can lead to respiratory failure, heart failure, pulmonary hypertension, and death. Pulmonologists and sleep specialists may be the first to see and diagnose patients with OHS in the outpatient setting, while other cases are diagnosed in the hospital when patients present with hypercapnic respiratory failure.

Screening for OHS usually involves measuring arterial blood gases, which is not standard practice in outpatient clinics. Patients often remain undiagnosed and untreated until late in the course of the disease, according to the American Thoracic Society, which in August published a new diagnosis and management guideline aiming to boost early diagnosis and reduce variability in treatment (Am J Respir Crit Care Med. 2019;200:3,e6–e24).

The guideline authors, led by Babak Mokhlesi, MD, of the University of Chicago, recommend a simpler screening method – measuring serum bicarbonate only – to rule out OHS in obese patients with nighttime breathing problems.

Serum bicarbonate should be measured in obese patients with sleep-disordered breathing and a low likelihood of OHS, Dr. Mokhlesi and colleagues recommend in the guideline. If serum bicarbonate is below 27 mmol/L, it is not necessary to conduct further testing as the patient is unlikely to have OHS.

In patients whose serum bicarbonate is higher than 27 mmol/L, or who are strongly suspected of having OHS at presentation because of severe obesity or other symptoms, arterial blood gases should be measured and a sleep study conducted. The guideline authors said that there is insufficient evidence to recommend that pulse oximetry be used in the diagnostic pathway for OHS.

First-line treatment for stable, ambulatory patients with OHS should be positive airway pressure during sleep, rather than noninvasive ventilation, Dr. Mokhlesi and colleagues concluded. For patients with comorbid obstructive sleep apnea – as many as 70% of OHS patients also have OSA – the first-line treatment should be continuous positive airway pressure (CPAP) at night, the guideline states.

Patients hospitalized with respiratory failure and suspected of having OHS should be discharged with noninvasive ventilation until diagnostic procedures can be performed, along with PAP titration in a sleep lab.

In patients initially treated with CPAP who remain symptomatic or whose blood carbon dioxide does not improve, noninvasive ventilation can be tried, the guidelines say. Finally, patients diagnosed with OHS should be guided to weight loss interventions with the aim of reducing body weight by 25%-30%. This can include referral for bariatric surgery in patients without contraindications.

Dr. Mokhlesi and colleagues acknowledged that all of the recommendations contained in the guideline are classed as “conditional,” based on the quality of evidence assessed.

The American Thoracic Society funded the study. Dr. Mokhlesi and 7 coauthors disclosed financial conflicts of interest, while an additional 13 coauthors had none. Disclosures can be found on the AJRCCM website.

SOURCE: Mokhlesi B et al. Am J Respir Crit Care Med. 2019;200:3,e6-e24

A blood test for elevated carbon dioxide may be used in screening adults for obesity hypoventilation syndrome, according to new guidelines.

Obese adults with sleep-disordered breathing and increased blood carbon dioxide levels during the day are likely to have obesity hypoventilation syndrome (OHS), a result of shallow or slow breathing that can lead to respiratory failure, heart failure, pulmonary hypertension, and death. Pulmonologists and sleep specialists may be the first to see and diagnose patients with OHS in the outpatient setting, while other cases are diagnosed in the hospital when patients present with hypercapnic respiratory failure.

Screening for OHS usually involves measuring arterial blood gases, which is not standard practice in outpatient clinics. Patients often remain undiagnosed and untreated until late in the course of the disease, according to the American Thoracic Society, which in August published a new diagnosis and management guideline aiming to boost early diagnosis and reduce variability in treatment (Am J Respir Crit Care Med. 2019;200:3,e6–e24).

The guideline authors, led by Babak Mokhlesi, MD, of the University of Chicago, recommend a simpler screening method – measuring serum bicarbonate only – to rule out OHS in obese patients with nighttime breathing problems.

Serum bicarbonate should be measured in obese patients with sleep-disordered breathing and a low likelihood of OHS, Dr. Mokhlesi and colleagues recommend in the guideline. If serum bicarbonate is below 27 mmol/L, it is not necessary to conduct further testing as the patient is unlikely to have OHS.

In patients whose serum bicarbonate is higher than 27 mmol/L, or who are strongly suspected of having OHS at presentation because of severe obesity or other symptoms, arterial blood gases should be measured and a sleep study conducted. The guideline authors said that there is insufficient evidence to recommend that pulse oximetry be used in the diagnostic pathway for OHS.

First-line treatment for stable, ambulatory patients with OHS should be positive airway pressure during sleep, rather than noninvasive ventilation, Dr. Mokhlesi and colleagues concluded. For patients with comorbid obstructive sleep apnea – as many as 70% of OHS patients also have OSA – the first-line treatment should be continuous positive airway pressure (CPAP) at night, the guideline states.

Patients hospitalized with respiratory failure and suspected of having OHS should be discharged with noninvasive ventilation until diagnostic procedures can be performed, along with PAP titration in a sleep lab.

In patients initially treated with CPAP who remain symptomatic or whose blood carbon dioxide does not improve, noninvasive ventilation can be tried, the guidelines say. Finally, patients diagnosed with OHS should be guided to weight loss interventions with the aim of reducing body weight by 25%-30%. This can include referral for bariatric surgery in patients without contraindications.

Dr. Mokhlesi and colleagues acknowledged that all of the recommendations contained in the guideline are classed as “conditional,” based on the quality of evidence assessed.

The American Thoracic Society funded the study. Dr. Mokhlesi and 7 coauthors disclosed financial conflicts of interest, while an additional 13 coauthors had none. Disclosures can be found on the AJRCCM website.

SOURCE: Mokhlesi B et al. Am J Respir Crit Care Med. 2019;200:3,e6-e24

A blood test for elevated carbon dioxide may be used in screening adults for obesity hypoventilation syndrome, according to new guidelines.

Obese adults with sleep-disordered breathing and increased blood carbon dioxide levels during the day are likely to have obesity hypoventilation syndrome (OHS), a result of shallow or slow breathing that can lead to respiratory failure, heart failure, pulmonary hypertension, and death. Pulmonologists and sleep specialists may be the first to see and diagnose patients with OHS in the outpatient setting, while other cases are diagnosed in the hospital when patients present with hypercapnic respiratory failure.

Screening for OHS usually involves measuring arterial blood gases, which is not standard practice in outpatient clinics. Patients often remain undiagnosed and untreated until late in the course of the disease, according to the American Thoracic Society, which in August published a new diagnosis and management guideline aiming to boost early diagnosis and reduce variability in treatment (Am J Respir Crit Care Med. 2019;200:3,e6–e24).

The guideline authors, led by Babak Mokhlesi, MD, of the University of Chicago, recommend a simpler screening method – measuring serum bicarbonate only – to rule out OHS in obese patients with nighttime breathing problems.

Serum bicarbonate should be measured in obese patients with sleep-disordered breathing and a low likelihood of OHS, Dr. Mokhlesi and colleagues recommend in the guideline. If serum bicarbonate is below 27 mmol/L, it is not necessary to conduct further testing as the patient is unlikely to have OHS.

In patients whose serum bicarbonate is higher than 27 mmol/L, or who are strongly suspected of having OHS at presentation because of severe obesity or other symptoms, arterial blood gases should be measured and a sleep study conducted. The guideline authors said that there is insufficient evidence to recommend that pulse oximetry be used in the diagnostic pathway for OHS.

First-line treatment for stable, ambulatory patients with OHS should be positive airway pressure during sleep, rather than noninvasive ventilation, Dr. Mokhlesi and colleagues concluded. For patients with comorbid obstructive sleep apnea – as many as 70% of OHS patients also have OSA – the first-line treatment should be continuous positive airway pressure (CPAP) at night, the guideline states.

Patients hospitalized with respiratory failure and suspected of having OHS should be discharged with noninvasive ventilation until diagnostic procedures can be performed, along with PAP titration in a sleep lab.

In patients initially treated with CPAP who remain symptomatic or whose blood carbon dioxide does not improve, noninvasive ventilation can be tried, the guidelines say. Finally, patients diagnosed with OHS should be guided to weight loss interventions with the aim of reducing body weight by 25%-30%. This can include referral for bariatric surgery in patients without contraindications.

Dr. Mokhlesi and colleagues acknowledged that all of the recommendations contained in the guideline are classed as “conditional,” based on the quality of evidence assessed.

The American Thoracic Society funded the study. Dr. Mokhlesi and 7 coauthors disclosed financial conflicts of interest, while an additional 13 coauthors had none. Disclosures can be found on the AJRCCM website.

SOURCE: Mokhlesi B et al. Am J Respir Crit Care Med. 2019;200:3,e6-e24

Noninvasive ventilation (NIV) supports patient’s breathing without the immediate need for tracheotomy or intubation. The Center for Medicare and Medicaid Services (CMS) defines respiratory assist devices (RAD) as bi-level devices with back-up respiratory rate capability, which provide noninvasive modes of ventilation for respiratory insufficiency or sleep-related respiratory disorders in a home or hospital setting (21 CFR 868.5895). These devices are smaller in size with provision of the external battery (if needed) but limited by inability to offer daytime ventilatory mode (ie, mouthpiece ventilation). Currently, respiratory assist devices have been in DMEPOS Competitive Bidding Program since 2011, (similar to PAP devices for sleep apnea syndromes), which puts a 13-month capped rental in which the patient gets the device, supplies, and services for 13 months subsequent to which patient owns the device and supplies are paid separately by CMS (https://www.dmecompetitivebid.com/cbic/cbic.nsf/DocsCat/Home).

On the other hand, CMS defines home mechanical ventilators (HMV) as life supporting/sustaining devices for patients of all age groups used in various settings, included but not limited to home, hospital, institutional setting, transportation, or wherever portability is needed. The ventilators have increased portability due to external and internal battery, provision of mouthpiece ventilation, and at least six pressure modes and three volumes modes. Currently, the ventilators are under the frequently and substantially serviced act [42 U.S.C. § 1395m(a)(3)]. Under this act, the patient never owns the device but the device, ancillary supplies, clinical support (trained respiratory therapists), and servicing of the device are included in the monthly payments, which can last indefinitely. Thus, ventilators have both higher reimbursement rates and uncapped rental periods; beneficiaries not only pay higher monthly co-payments for these devices but also pay over a longer rental period. Nonetheless, these services are vital in keeping a certain subset of patients comfortable at home and out of higher cost settings. The current populations that directly benefit from this service are patients with polio, amyotrophic lateral sclerosis, muscular dystrophies, spinal muscle atrophy, thoracic restrictive disorder, and chronic hypercapnic respiratory failure due to COPD, to name a few. Thus, HMV has been vital in “freeing” these frail and vulnerable patient populations from their hospital beds, improving the quality of life, as well as mortality.

With the advent of technologic advancements, HMV, especially the noninvasive pressure support ventilator, is now capable of doing multiple modes, including CPAP, RAD modes, and ventilator modes. This could create a potential of abuse when the durable medical equipment supplier bills CMS for the ventilator but clinically, a lower cost CPAP, auto bi-level PAP, or RAD is indicated. The 2016 report from the Office of Inspector General (OIG) noted that CMS paid 85 times more claims for noninvasive pressure support ventilators in 2015 than in 2009 (from $3.8 million to $340 million). [https://tinyurl.com/y3ckskrb]. Expenditure increased from 2014 to 2015 alone accounted for 47% of the entire $337 million increase from 2009 to 2015. But, the report could not implicate reduced prices for CPAP devices and RADs under the Competitive Bidding Program to be driving increased billing for ventilators. They did find that the diagnoses used for these claims have shifted dramatically from neuromuscular diseases to other chronic respiratory conditions.

Since then, in January 2016, CMS consolidated billing codes for ventilators, and also reduced the reimbursement amount for noninvasive pressure support ventilators. After this change, between 2015 and 2016, median monthly rental rate of products decreased from $1,561 to $1,055; a reduction of 32% [https://tinyurl.com/y3ckskrb]. CMS presently is proposing to include HMV in the competitive bidding program to help with misuse and cost reduction. But proposed addition of the home ventilators in competitive bidding risks elimination of the vital services that are so important to keep a very “vulnerable and frail” population out of higher cost facilities. Because of this, CMS would see increased costs due to frequent emergency rooms visits, frequent intubations, intensive care unit stays, and admissions to long-term care at skilled nursing on one hand, but negatively impacting the quality of life of these patients on the other hand. This addition would have serious unintended consequences on Medicaid recipients, especially the pediatric population.

As a clinical guide, RADs are used for similar clinical conditions as HMV, but are meant for less severe respiratory conditions. Ideally, getting a RAD device for a patient should be governed by the physician’s clinical judgment rather than rigorous qualification criteria, nonetheless current RAD coverage policy in not only difficult but includes unnecessary qualification criteria, and as a result pushing the patient towards more costly ventilators. Unfortunately, CMS policies have not kept up with the technological advances of noninvasive ventilation. This has led to increased costs and utilization of noninvasive ventilators. In our opinion, including noninvasive ventilators in competitive bidding to reduce cost utilization is not the solution.

CMS needs to work with medical providers, beneficiaries, and various stakeholders to revise the current respiratory assist device and home mechanical ventilator guidelines in order to ensure that the appropriate patient is eligible for the correct device, without putting a very vulnerable patient population at risk.
 

Dr. Sahni is Clinical Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Illinois at Chicago; Dr. Wolfe is Associate Professor of Medicine (Pulmonary & Critical Care) and Neurology (Sleep Medicine), Northwestern University, Chicago, Illinois.

Noninvasive ventilation (NIV) supports patient’s breathing without the immediate need for tracheotomy or intubation. The Center for Medicare and Medicaid Services (CMS) defines respiratory assist devices (RAD) as bi-level devices with back-up respiratory rate capability, which provide noninvasive modes of ventilation for respiratory insufficiency or sleep-related respiratory disorders in a home or hospital setting (21 CFR 868.5895). These devices are smaller in size with provision of the external battery (if needed) but limited by inability to offer daytime ventilatory mode (ie, mouthpiece ventilation). Currently, respiratory assist devices have been in DMEPOS Competitive Bidding Program since 2011, (similar to PAP devices for sleep apnea syndromes), which puts a 13-month capped rental in which the patient gets the device, supplies, and services for 13 months subsequent to which patient owns the device and supplies are paid separately by CMS (https://www.dmecompetitivebid.com/cbic/cbic.nsf/DocsCat/Home).

On the other hand, CMS defines home mechanical ventilators (HMV) as life supporting/sustaining devices for patients of all age groups used in various settings, included but not limited to home, hospital, institutional setting, transportation, or wherever portability is needed. The ventilators have increased portability due to external and internal battery, provision of mouthpiece ventilation, and at least six pressure modes and three volumes modes. Currently, the ventilators are under the frequently and substantially serviced act [42 U.S.C. § 1395m(a)(3)]. Under this act, the patient never owns the device but the device, ancillary supplies, clinical support (trained respiratory therapists), and servicing of the device are included in the monthly payments, which can last indefinitely. Thus, ventilators have both higher reimbursement rates and uncapped rental periods; beneficiaries not only pay higher monthly co-payments for these devices but also pay over a longer rental period. Nonetheless, these services are vital in keeping a certain subset of patients comfortable at home and out of higher cost settings. The current populations that directly benefit from this service are patients with polio, amyotrophic lateral sclerosis, muscular dystrophies, spinal muscle atrophy, thoracic restrictive disorder, and chronic hypercapnic respiratory failure due to COPD, to name a few. Thus, HMV has been vital in “freeing” these frail and vulnerable patient populations from their hospital beds, improving the quality of life, as well as mortality.

With the advent of technologic advancements, HMV, especially the noninvasive pressure support ventilator, is now capable of doing multiple modes, including CPAP, RAD modes, and ventilator modes. This could create a potential of abuse when the durable medical equipment supplier bills CMS for the ventilator but clinically, a lower cost CPAP, auto bi-level PAP, or RAD is indicated. The 2016 report from the Office of Inspector General (OIG) noted that CMS paid 85 times more claims for noninvasive pressure support ventilators in 2015 than in 2009 (from $3.8 million to $340 million). [https://tinyurl.com/y3ckskrb]. Expenditure increased from 2014 to 2015 alone accounted for 47% of the entire $337 million increase from 2009 to 2015. But, the report could not implicate reduced prices for CPAP devices and RADs under the Competitive Bidding Program to be driving increased billing for ventilators. They did find that the diagnoses used for these claims have shifted dramatically from neuromuscular diseases to other chronic respiratory conditions.

Since then, in January 2016, CMS consolidated billing codes for ventilators, and also reduced the reimbursement amount for noninvasive pressure support ventilators. After this change, between 2015 and 2016, median monthly rental rate of products decreased from $1,561 to $1,055; a reduction of 32% [https://tinyurl.com/y3ckskrb]. CMS presently is proposing to include HMV in the competitive bidding program to help with misuse and cost reduction. But proposed addition of the home ventilators in competitive bidding risks elimination of the vital services that are so important to keep a very “vulnerable and frail” population out of higher cost facilities. Because of this, CMS would see increased costs due to frequent emergency rooms visits, frequent intubations, intensive care unit stays, and admissions to long-term care at skilled nursing on one hand, but negatively impacting the quality of life of these patients on the other hand. This addition would have serious unintended consequences on Medicaid recipients, especially the pediatric population.

As a clinical guide, RADs are used for similar clinical conditions as HMV, but are meant for less severe respiratory conditions. Ideally, getting a RAD device for a patient should be governed by the physician’s clinical judgment rather than rigorous qualification criteria, nonetheless current RAD coverage policy in not only difficult but includes unnecessary qualification criteria, and as a result pushing the patient towards more costly ventilators. Unfortunately, CMS policies have not kept up with the technological advances of noninvasive ventilation. This has led to increased costs and utilization of noninvasive ventilators. In our opinion, including noninvasive ventilators in competitive bidding to reduce cost utilization is not the solution.

CMS needs to work with medical providers, beneficiaries, and various stakeholders to revise the current respiratory assist device and home mechanical ventilator guidelines in order to ensure that the appropriate patient is eligible for the correct device, without putting a very vulnerable patient population at risk.
 

Dr. Sahni is Clinical Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Illinois at Chicago; Dr. Wolfe is Associate Professor of Medicine (Pulmonary & Critical Care) and Neurology (Sleep Medicine), Northwestern University, Chicago, Illinois.

Noninvasive ventilation (NIV) supports patient’s breathing without the immediate need for tracheotomy or intubation. The Center for Medicare and Medicaid Services (CMS) defines respiratory assist devices (RAD) as bi-level devices with back-up respiratory rate capability, which provide noninvasive modes of ventilation for respiratory insufficiency or sleep-related respiratory disorders in a home or hospital setting (21 CFR 868.5895). These devices are smaller in size with provision of the external battery (if needed) but limited by inability to offer daytime ventilatory mode (ie, mouthpiece ventilation). Currently, respiratory assist devices have been in DMEPOS Competitive Bidding Program since 2011, (similar to PAP devices for sleep apnea syndromes), which puts a 13-month capped rental in which the patient gets the device, supplies, and services for 13 months subsequent to which patient owns the device and supplies are paid separately by CMS (https://www.dmecompetitivebid.com/cbic/cbic.nsf/DocsCat/Home).

On the other hand, CMS defines home mechanical ventilators (HMV) as life supporting/sustaining devices for patients of all age groups used in various settings, included but not limited to home, hospital, institutional setting, transportation, or wherever portability is needed. The ventilators have increased portability due to external and internal battery, provision of mouthpiece ventilation, and at least six pressure modes and three volumes modes. Currently, the ventilators are under the frequently and substantially serviced act [42 U.S.C. § 1395m(a)(3)]. Under this act, the patient never owns the device but the device, ancillary supplies, clinical support (trained respiratory therapists), and servicing of the device are included in the monthly payments, which can last indefinitely. Thus, ventilators have both higher reimbursement rates and uncapped rental periods; beneficiaries not only pay higher monthly co-payments for these devices but also pay over a longer rental period. Nonetheless, these services are vital in keeping a certain subset of patients comfortable at home and out of higher cost settings. The current populations that directly benefit from this service are patients with polio, amyotrophic lateral sclerosis, muscular dystrophies, spinal muscle atrophy, thoracic restrictive disorder, and chronic hypercapnic respiratory failure due to COPD, to name a few. Thus, HMV has been vital in “freeing” these frail and vulnerable patient populations from their hospital beds, improving the quality of life, as well as mortality.

With the advent of technologic advancements, HMV, especially the noninvasive pressure support ventilator, is now capable of doing multiple modes, including CPAP, RAD modes, and ventilator modes. This could create a potential of abuse when the durable medical equipment supplier bills CMS for the ventilator but clinically, a lower cost CPAP, auto bi-level PAP, or RAD is indicated. The 2016 report from the Office of Inspector General (OIG) noted that CMS paid 85 times more claims for noninvasive pressure support ventilators in 2015 than in 2009 (from $3.8 million to $340 million). [https://tinyurl.com/y3ckskrb]. Expenditure increased from 2014 to 2015 alone accounted for 47% of the entire $337 million increase from 2009 to 2015. But, the report could not implicate reduced prices for CPAP devices and RADs under the Competitive Bidding Program to be driving increased billing for ventilators. They did find that the diagnoses used for these claims have shifted dramatically from neuromuscular diseases to other chronic respiratory conditions.

Since then, in January 2016, CMS consolidated billing codes for ventilators, and also reduced the reimbursement amount for noninvasive pressure support ventilators. After this change, between 2015 and 2016, median monthly rental rate of products decreased from $1,561 to $1,055; a reduction of 32% [https://tinyurl.com/y3ckskrb]. CMS presently is proposing to include HMV in the competitive bidding program to help with misuse and cost reduction. But proposed addition of the home ventilators in competitive bidding risks elimination of the vital services that are so important to keep a very “vulnerable and frail” population out of higher cost facilities. Because of this, CMS would see increased costs due to frequent emergency rooms visits, frequent intubations, intensive care unit stays, and admissions to long-term care at skilled nursing on one hand, but negatively impacting the quality of life of these patients on the other hand. This addition would have serious unintended consequences on Medicaid recipients, especially the pediatric population.

As a clinical guide, RADs are used for similar clinical conditions as HMV, but are meant for less severe respiratory conditions. Ideally, getting a RAD device for a patient should be governed by the physician’s clinical judgment rather than rigorous qualification criteria, nonetheless current RAD coverage policy in not only difficult but includes unnecessary qualification criteria, and as a result pushing the patient towards more costly ventilators. Unfortunately, CMS policies have not kept up with the technological advances of noninvasive ventilation. This has led to increased costs and utilization of noninvasive ventilators. In our opinion, including noninvasive ventilators in competitive bidding to reduce cost utilization is not the solution.

CMS needs to work with medical providers, beneficiaries, and various stakeholders to revise the current respiratory assist device and home mechanical ventilator guidelines in order to ensure that the appropriate patient is eligible for the correct device, without putting a very vulnerable patient population at risk.
 

Dr. Sahni is Clinical Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Illinois at Chicago; Dr. Wolfe is Associate Professor of Medicine (Pulmonary & Critical Care) and Neurology (Sleep Medicine), Northwestern University, Chicago, Illinois.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

DEFINITION

Obstructive sleep apnea (OSA) occurs when there are recurrent episodes of upper airway collapse and obstruction during sleep associated with arousals with or without oxygen desaturations. The oropharynx in the back of the throat collapses during OSA events to cause arousal or oxygen desaturation or both resulting in fragmented sleep.

PREVALENCE

Studies reveal OSA is prevalent. A 2015 study in Switzerland reported 50% of men and 23% of women had at least moderate OSA.¹ In 2002, the Sleep Heart Health study found that 24% of men and 9% of women have at least mild OSA.² In the Wisconsin Sleep Study Cohort, it was reported that 10% of men and 3% of women age 30 to 49 have at least moderate OSA, while 17% of men and 9% of women age 50 to 70 have at least moderate OSA.³ OSA is highly underrecognized and it is estimated that 82% of men and 93% of women in the United States with OSA are undiagnosed.⁴

SYMPTOMS

RISK FACTORS

The risk of OSA is influenced by unmodifiable and modifiable factors. Unmodifiable risk factors include male sex, age, and race. Genetic predisposition or a family history of OSA as well as cranial facial anatomy resulting in narrow airways may impart higher risk of OSA. Modifiable risk factors include obesity, medications that cause muscle relaxation and narrowing of the airway (opiates, benzodiazepines, alcohol), endocrine disorders (hypothyroidism, polycystic ovarian syndrome), smoking, and nasal congestion or obstruction.⁶

Sex

Men are at higher risk for OSA than women although once women reach menopause they have a risk similar to men. Postmenopausal women on hormone replacement therapy were found to have lower rates of OSA, suggesting that loss of hormones results in greater risk of OSA.^7,8 Women also have more OSA during rapid eye movement (REM) sleep and less OSA when sleeping supine, whereas most men have OSA when sleeping supine.^9,10 OSA is less severe in women compared with men of similar body mass index (BMI).¹¹ Symptoms vary in men and women: snoring and witnessed apneas are more common in men whereas insomnia and excessive daytime sleepiness are more common in women.¹¹ This may account for delayed diagnosis and the higher mortality in women compared with men.

Age

The risk of OSA increases with age. In a study of men 65 or older, the prevalence of moderate OSA was 23% in men younger than 72 and 30% in men older than 80.¹² By comparison, the prevalence of moderate OSA in men 30 to 40 years was 10%.³ Increased risk of OSA with age may be due to age-related reduction in slow wave sleep (ie, deep sleep), which is protective against sleep-disordered breathing and airway collapse.¹³ Older adults are also less symptomatic, reporting less daytime sleepiness and fatigue.¹⁴

Race

The Sleep Heart Health Study found a slightly increased risk of moderate to severe OSA in blacks (20%) and American Indians (23%) compared with whites (17%).² Another study showed the  prevalence of OSA was 30% in whites, 32% in blacks, 38% in Hispanics, and 39% in Chinese individuals.¹⁵ A higher prevalence of OSA in young blacks (≤ 25 years) compared with whites was reported,¹⁶ although another study found no differences based on race in older patients.¹⁷ These differences among racial groups may be due to variations in craniofacial anatomy.

Obesity

There is a correlation between increased risk of OSA and obesity (BMI > 30 kg/m²) and its correlates of greater waist-to-hip ratio and neck circumference.² A 10% increase in body weight results in a sixfold increase in moderate to severe OSA and increases the apnea–hypopnea index (AHI; number of breath pauses or respiratory events per hour) by 32% whereas a 10% decrease in weight decreases the AHI by 26%.¹⁸

COMORBIDITIES

OSA is associated with a number of comorbid conditions including stroke, myocardial infarction, hypertension, hyperlipidemia, glucose intolerance, diabetes, arrhythmias including atrial fibrillation, pulmonary hypertension, congestive heart failure, and depression. Patients with moderate or severe OSA are at higher risk of these comorbid conditions.¹⁹

Patients with cardiovascular disease have a very high prevalence of OSA: hypertension (83% mild to 30% moderate to severe OSA), heart failure (55% to 12%), arrhythmias (50% to 20%), stroke (75% to 57%), and coronary heart disease (65% to 38%).²⁰ Increased awareness and early diagnosis of OSA is critical to reducing cardiovascular disease burden.

Sleep history

A sleep history starts with determining the patient’s total sleep time, based on time to bed, time to fall asleep, and time of wake up, including any difficulty falling asleep, staying asleep, or daytime naps.

Symptoms. Daytime naps generally indicate a sleep deficit or sleep that is not refreshing. A review of sleep and daytime symptoms associated with OSA (Table 1) helps determine if excessive daytime sleepiness or unrefreshing sleep is out of proportion with the amount of sleep the patient is getting at night.

Some patients with OSA may have memory or concentration issues or feel like they have attention deficit disorder. In fact some patients are diagnosed with attention deficit disorder because of their insufficient sleep or unrefreshing sleep.

Drowsy driving is a special concern in patients with untreated OSA and sleep deprivation. Many patients have drowsy driving episodes or difficulty staying awake during long-distance driving. Caffeine use is also important information as excessive caffeine may be used to combat sleepiness during the day.

The Epworth Sleepiness Scale is a clinical screening tool that presents 8 situations for patients to consider and indicate their level of sleepiness and likelihood of falling asleep (never = 0; slight = 1; moderate = 2, high = 3).^21,22 A total score ≥ 10 is considered abnormal in that the patient is excessively sleepy compared with most people.

Risk factors and comorbid conditions. OSA risk factors and comorbidities, including a BMI obesity assessment, should be reviewed with patients. Nasal congestion or mouth breathing especially at night could be due to airway obstruction increasing the risk of OSA. Family history of OSA, tobacco, alcohol use, other medical conditions, and medications should also be discussed.

Physical examination

• Neck circumference greater than 17 inches for men or greater than 16 inches for women
• BMI greater than 30
• Friedman class tongue position class 3 or greater (Figure 1)
• Mouth features (present/enlarged tonsils, macroglossia, jaw misalignment)
• Nasal abnormalities (turbinate hypertrophy, deviated septum).⁵

Patients with Friedman palate positions class 3 and 4 have a higher risk of OSA due to airway crowding during sleep when the airway naturally collapses a little and is even more restricted.

Narrow airways or oropharyngeal crowding can also be due to a swollen, enlarged, or elongated uvula; present or enlarged tonsils; or lateral wall narrowing. Alone or in combination, these features can contribute to airway obstruction.

Other signs in the mouth suggestive of obstruction are macroglossia (enlarged tongue) and tongue ridging. Tongue ridging or scalloping impressions typically occur during sleep and are caused by the tongue moving forward to open the airway and pressing against the teeth.

Retrognathia (lower jaw offset behind upper jaw) can narrow the airway and increase the risk of OSA as can a high arch palate, overbite (upper teeth forward), or overjet (upper teeth over the top of lower teeth).

A nasal examination for nasal valve collapse (ie, nostril collapses with inhalation), deviated septum, and inferior turbinate hypertrophy impart an increased risk of OSA.

Screening tools

In addition to the Epworth Sleepiness Scale, the STOP-BANG questionnaire can help determine if a patient should be tested further for OSA. The STOP-BANG questionnaire consists of 8 yes-no questions where more than 2 yes responses indicate the patient is at higher risk for moderate to severe OSA (93% sensitivity): Snore, Tired, Observed stopped breathing, high blood Pressure, BMI > 35 kg/m², Age > 50, Neck > 15.75 inches, Gender = male).²³

Polysomnography

Home sleep apnea test

HSATs record 4 to 7 parameters including airflow (thermal and nasal pressure), effort (inductive ple­thysmography), and oximetry. No electroencephalogram is used, so sleep is not recorded; it is assumed the patient is sleeping for the duration of the test. As such, respiratory events are based on oxygen desaturations and reduced airflow and pressure as well as chest and abdomen effort. The raw data are edited and manually scored and reviewed by a sleep specialist.²⁵

Although the HSAT is convenient for many patients, it underestimates the severity of sleep-related breathing disorders. HSAT is intended to confirm OSA in patients with a high likelihood of OSA based on their sleep history.²⁶ It is ideally employed for adult patients with no major medical problems or other sleep problems who are at high risk for moderate to severe OSA based on the STOP-BANG questionnaire or those with daytime sleepiness and 2 of the 3 symptoms of snoring, witnessed apnea, or hypertension.²⁷

A negative or inconclusive HSAT warrants a PSG to ensure the patient does not have OSA. Use of HSAT is contraindicated in patients with

• Significant cardiopulmonary disease
• Potential weakness due to a neuro­muscular condition
• Awake hypoventilation or high risk for sleep-related hypoventilation (severe obesity)
• History of stroke
• Chronic opioid use
• Severe insomnia
• Symptoms of other significant sleep disorders
• Environmental/personal factors that would preclude adequate acquisition and interpretation of data (disruptions from children, pets, other factors).²⁷

DIAGNOSTIC CRITERIA

Respiratory events captured on a PSG or HSAT

The OSA diagnostic criteria are based on the occurrence of obstructive respiratory events recorded during sleep such as apneas, hypopneas, and respiratory event-related arousals.

Hypopneas. A hypopnea is a respiratory event resulting in reduced airflow. The America Association of Sleep Medicine’s preferred definition is a reduction in nasal pressure of at least 30% for 10 seconds or longer with 3% or greater oxygen desaturation or an electroencephalogram arousal. Another acceptable definition is at least 30% reduction in thoracoabdominal movement or airflow with 4% or greater oxygen desaturation, which is used by the Centers for Medicare and Medicaid Services and other insurers.^29,30 Hypopnea requires greater oxygen desaturation and is not dependent on arousals, which can sometimes make it more challenging to identify OSA (Figure 2).

Respiratory event-related arousals. Respiratory event-related arousals are respiratory events not meeting apnea or hypopnea criteria. They are measured as a sequence of breaths of 10 or more seconds with increasing respiratory effort or flattening of the nasal pressure waveform leading to arousal (Figure 2).²⁹ Respiratory event-related arousals are disruptive to sleep and have many of the same consequences as apneas and hypopneas.

Severity

SUMMARY

OSA results from airway collapse and obstruction during sleep, often causing arousal from sleep with or without oxygen desaturation. The prevalence of OSA is underestimated and it is underdiagnosed despite known risk factors and comorbid conditions. Screening for OSA with a sleep history, simple upper airway examination, and quick validated screening tool like the STOP-BANG or Epworth Sleepiness Scale aid in identifying the need for testing for OSA. A laboratory sleep study with a PSG can confirm the diagnosis and severity of OSA. HSATs are available to confirm the diagnosis of OSA in patients at high risk for moderate to severe OSA.

DEFINITION

Obstructive sleep apnea (OSA) occurs when there are recurrent episodes of upper airway collapse and obstruction during sleep associated with arousals with or without oxygen desaturations. The oropharynx in the back of the throat collapses during OSA events to cause arousal or oxygen desaturation or both resulting in fragmented sleep.

PREVALENCE

Studies reveal OSA is prevalent. A 2015 study in Switzerland reported 50% of men and 23% of women had at least moderate OSA.¹ In 2002, the Sleep Heart Health study found that 24% of men and 9% of women have at least mild OSA.² In the Wisconsin Sleep Study Cohort, it was reported that 10% of men and 3% of women age 30 to 49 have at least moderate OSA, while 17% of men and 9% of women age 50 to 70 have at least moderate OSA.³ OSA is highly underrecognized and it is estimated that 82% of men and 93% of women in the United States with OSA are undiagnosed.⁴

SYMPTOMS

RISK FACTORS

The risk of OSA is influenced by unmodifiable and modifiable factors. Unmodifiable risk factors include male sex, age, and race. Genetic predisposition or a family history of OSA as well as cranial facial anatomy resulting in narrow airways may impart higher risk of OSA. Modifiable risk factors include obesity, medications that cause muscle relaxation and narrowing of the airway (opiates, benzodiazepines, alcohol), endocrine disorders (hypothyroidism, polycystic ovarian syndrome), smoking, and nasal congestion or obstruction.⁶

Sex

Men are at higher risk for OSA than women although once women reach menopause they have a risk similar to men. Postmenopausal women on hormone replacement therapy were found to have lower rates of OSA, suggesting that loss of hormones results in greater risk of OSA.^7,8 Women also have more OSA during rapid eye movement (REM) sleep and less OSA when sleeping supine, whereas most men have OSA when sleeping supine.^9,10 OSA is less severe in women compared with men of similar body mass index (BMI).¹¹ Symptoms vary in men and women: snoring and witnessed apneas are more common in men whereas insomnia and excessive daytime sleepiness are more common in women.¹¹ This may account for delayed diagnosis and the higher mortality in women compared with men.

Age

The risk of OSA increases with age. In a study of men 65 or older, the prevalence of moderate OSA was 23% in men younger than 72 and 30% in men older than 80.¹² By comparison, the prevalence of moderate OSA in men 30 to 40 years was 10%.³ Increased risk of OSA with age may be due to age-related reduction in slow wave sleep (ie, deep sleep), which is protective against sleep-disordered breathing and airway collapse.¹³ Older adults are also less symptomatic, reporting less daytime sleepiness and fatigue.¹⁴

Race

The Sleep Heart Health Study found a slightly increased risk of moderate to severe OSA in blacks (20%) and American Indians (23%) compared with whites (17%).² Another study showed the  prevalence of OSA was 30% in whites, 32% in blacks, 38% in Hispanics, and 39% in Chinese individuals.¹⁵ A higher prevalence of OSA in young blacks (≤ 25 years) compared with whites was reported,¹⁶ although another study found no differences based on race in older patients.¹⁷ These differences among racial groups may be due to variations in craniofacial anatomy.

Obesity

There is a correlation between increased risk of OSA and obesity (BMI > 30 kg/m²) and its correlates of greater waist-to-hip ratio and neck circumference.² A 10% increase in body weight results in a sixfold increase in moderate to severe OSA and increases the apnea–hypopnea index (AHI; number of breath pauses or respiratory events per hour) by 32% whereas a 10% decrease in weight decreases the AHI by 26%.¹⁸

COMORBIDITIES

OSA is associated with a number of comorbid conditions including stroke, myocardial infarction, hypertension, hyperlipidemia, glucose intolerance, diabetes, arrhythmias including atrial fibrillation, pulmonary hypertension, congestive heart failure, and depression. Patients with moderate or severe OSA are at higher risk of these comorbid conditions.¹⁹

Patients with cardiovascular disease have a very high prevalence of OSA: hypertension (83% mild to 30% moderate to severe OSA), heart failure (55% to 12%), arrhythmias (50% to 20%), stroke (75% to 57%), and coronary heart disease (65% to 38%).²⁰ Increased awareness and early diagnosis of OSA is critical to reducing cardiovascular disease burden.

Sleep history

A sleep history starts with determining the patient’s total sleep time, based on time to bed, time to fall asleep, and time of wake up, including any difficulty falling asleep, staying asleep, or daytime naps.

Symptoms. Daytime naps generally indicate a sleep deficit or sleep that is not refreshing. A review of sleep and daytime symptoms associated with OSA (Table 1) helps determine if excessive daytime sleepiness or unrefreshing sleep is out of proportion with the amount of sleep the patient is getting at night.

Some patients with OSA may have memory or concentration issues or feel like they have attention deficit disorder. In fact some patients are diagnosed with attention deficit disorder because of their insufficient sleep or unrefreshing sleep.

Drowsy driving is a special concern in patients with untreated OSA and sleep deprivation. Many patients have drowsy driving episodes or difficulty staying awake during long-distance driving. Caffeine use is also important information as excessive caffeine may be used to combat sleepiness during the day.

The Epworth Sleepiness Scale is a clinical screening tool that presents 8 situations for patients to consider and indicate their level of sleepiness and likelihood of falling asleep (never = 0; slight = 1; moderate = 2, high = 3).^21,22 A total score ≥ 10 is considered abnormal in that the patient is excessively sleepy compared with most people.

Risk factors and comorbid conditions. OSA risk factors and comorbidities, including a BMI obesity assessment, should be reviewed with patients. Nasal congestion or mouth breathing especially at night could be due to airway obstruction increasing the risk of OSA. Family history of OSA, tobacco, alcohol use, other medical conditions, and medications should also be discussed.

Physical examination

• Neck circumference greater than 17 inches for men or greater than 16 inches for women
• BMI greater than 30
• Friedman class tongue position class 3 or greater (Figure 1)
• Mouth features (present/enlarged tonsils, macroglossia, jaw misalignment)
• Nasal abnormalities (turbinate hypertrophy, deviated septum).⁵

Patients with Friedman palate positions class 3 and 4 have a higher risk of OSA due to airway crowding during sleep when the airway naturally collapses a little and is even more restricted.

Narrow airways or oropharyngeal crowding can also be due to a swollen, enlarged, or elongated uvula; present or enlarged tonsils; or lateral wall narrowing. Alone or in combination, these features can contribute to airway obstruction.

Other signs in the mouth suggestive of obstruction are macroglossia (enlarged tongue) and tongue ridging. Tongue ridging or scalloping impressions typically occur during sleep and are caused by the tongue moving forward to open the airway and pressing against the teeth.

Retrognathia (lower jaw offset behind upper jaw) can narrow the airway and increase the risk of OSA as can a high arch palate, overbite (upper teeth forward), or overjet (upper teeth over the top of lower teeth).

A nasal examination for nasal valve collapse (ie, nostril collapses with inhalation), deviated septum, and inferior turbinate hypertrophy impart an increased risk of OSA.

Screening tools

In addition to the Epworth Sleepiness Scale, the STOP-BANG questionnaire can help determine if a patient should be tested further for OSA. The STOP-BANG questionnaire consists of 8 yes-no questions where more than 2 yes responses indicate the patient is at higher risk for moderate to severe OSA (93% sensitivity): Snore, Tired, Observed stopped breathing, high blood Pressure, BMI > 35 kg/m², Age > 50, Neck > 15.75 inches, Gender = male).²³

Polysomnography

Home sleep apnea test

HSATs record 4 to 7 parameters including airflow (thermal and nasal pressure), effort (inductive ple­thysmography), and oximetry. No electroencephalogram is used, so sleep is not recorded; it is assumed the patient is sleeping for the duration of the test. As such, respiratory events are based on oxygen desaturations and reduced airflow and pressure as well as chest and abdomen effort. The raw data are edited and manually scored and reviewed by a sleep specialist.²⁵

Although the HSAT is convenient for many patients, it underestimates the severity of sleep-related breathing disorders. HSAT is intended to confirm OSA in patients with a high likelihood of OSA based on their sleep history.²⁶ It is ideally employed for adult patients with no major medical problems or other sleep problems who are at high risk for moderate to severe OSA based on the STOP-BANG questionnaire or those with daytime sleepiness and 2 of the 3 symptoms of snoring, witnessed apnea, or hypertension.²⁷

A negative or inconclusive HSAT warrants a PSG to ensure the patient does not have OSA. Use of HSAT is contraindicated in patients with

• Significant cardiopulmonary disease
• Potential weakness due to a neuro­muscular condition
• Awake hypoventilation or high risk for sleep-related hypoventilation (severe obesity)
• History of stroke
• Chronic opioid use
• Severe insomnia
• Symptoms of other significant sleep disorders
• Environmental/personal factors that would preclude adequate acquisition and interpretation of data (disruptions from children, pets, other factors).²⁷

DIAGNOSTIC CRITERIA

Respiratory events captured on a PSG or HSAT

The OSA diagnostic criteria are based on the occurrence of obstructive respiratory events recorded during sleep such as apneas, hypopneas, and respiratory event-related arousals.

Hypopneas. A hypopnea is a respiratory event resulting in reduced airflow. The America Association of Sleep Medicine’s preferred definition is a reduction in nasal pressure of at least 30% for 10 seconds or longer with 3% or greater oxygen desaturation or an electroencephalogram arousal. Another acceptable definition is at least 30% reduction in thoracoabdominal movement or airflow with 4% or greater oxygen desaturation, which is used by the Centers for Medicare and Medicaid Services and other insurers.^29,30 Hypopnea requires greater oxygen desaturation and is not dependent on arousals, which can sometimes make it more challenging to identify OSA (Figure 2).

Respiratory event-related arousals. Respiratory event-related arousals are respiratory events not meeting apnea or hypopnea criteria. They are measured as a sequence of breaths of 10 or more seconds with increasing respiratory effort or flattening of the nasal pressure waveform leading to arousal (Figure 2).²⁹ Respiratory event-related arousals are disruptive to sleep and have many of the same consequences as apneas and hypopneas.

Severity

SUMMARY

OSA results from airway collapse and obstruction during sleep, often causing arousal from sleep with or without oxygen desaturation. The prevalence of OSA is underestimated and it is underdiagnosed despite known risk factors and comorbid conditions. Screening for OSA with a sleep history, simple upper airway examination, and quick validated screening tool like the STOP-BANG or Epworth Sleepiness Scale aid in identifying the need for testing for OSA. A laboratory sleep study with a PSG can confirm the diagnosis and severity of OSA. HSATs are available to confirm the diagnosis of OSA in patients at high risk for moderate to severe OSA.

DEFINITION

Obstructive sleep apnea (OSA) occurs when there are recurrent episodes of upper airway collapse and obstruction during sleep associated with arousals with or without oxygen desaturations. The oropharynx in the back of the throat collapses during OSA events to cause arousal or oxygen desaturation or both resulting in fragmented sleep.

PREVALENCE

Studies reveal OSA is prevalent. A 2015 study in Switzerland reported 50% of men and 23% of women had at least moderate OSA.¹ In 2002, the Sleep Heart Health study found that 24% of men and 9% of women have at least mild OSA.² In the Wisconsin Sleep Study Cohort, it was reported that 10% of men and 3% of women age 30 to 49 have at least moderate OSA, while 17% of men and 9% of women age 50 to 70 have at least moderate OSA.³ OSA is highly underrecognized and it is estimated that 82% of men and 93% of women in the United States with OSA are undiagnosed.⁴

SYMPTOMS

RISK FACTORS

The risk of OSA is influenced by unmodifiable and modifiable factors. Unmodifiable risk factors include male sex, age, and race. Genetic predisposition or a family history of OSA as well as cranial facial anatomy resulting in narrow airways may impart higher risk of OSA. Modifiable risk factors include obesity, medications that cause muscle relaxation and narrowing of the airway (opiates, benzodiazepines, alcohol), endocrine disorders (hypothyroidism, polycystic ovarian syndrome), smoking, and nasal congestion or obstruction.⁶

Sex

Men are at higher risk for OSA than women although once women reach menopause they have a risk similar to men. Postmenopausal women on hormone replacement therapy were found to have lower rates of OSA, suggesting that loss of hormones results in greater risk of OSA.^7,8 Women also have more OSA during rapid eye movement (REM) sleep and less OSA when sleeping supine, whereas most men have OSA when sleeping supine.^9,10 OSA is less severe in women compared with men of similar body mass index (BMI).¹¹ Symptoms vary in men and women: snoring and witnessed apneas are more common in men whereas insomnia and excessive daytime sleepiness are more common in women.¹¹ This may account for delayed diagnosis and the higher mortality in women compared with men.

Age

The risk of OSA increases with age. In a study of men 65 or older, the prevalence of moderate OSA was 23% in men younger than 72 and 30% in men older than 80.¹² By comparison, the prevalence of moderate OSA in men 30 to 40 years was 10%.³ Increased risk of OSA with age may be due to age-related reduction in slow wave sleep (ie, deep sleep), which is protective against sleep-disordered breathing and airway collapse.¹³ Older adults are also less symptomatic, reporting less daytime sleepiness and fatigue.¹⁴

Race

The Sleep Heart Health Study found a slightly increased risk of moderate to severe OSA in blacks (20%) and American Indians (23%) compared with whites (17%).² Another study showed the  prevalence of OSA was 30% in whites, 32% in blacks, 38% in Hispanics, and 39% in Chinese individuals.¹⁵ A higher prevalence of OSA in young blacks (≤ 25 years) compared with whites was reported,¹⁶ although another study found no differences based on race in older patients.¹⁷ These differences among racial groups may be due to variations in craniofacial anatomy.

Obesity

There is a correlation between increased risk of OSA and obesity (BMI > 30 kg/m²) and its correlates of greater waist-to-hip ratio and neck circumference.² A 10% increase in body weight results in a sixfold increase in moderate to severe OSA and increases the apnea–hypopnea index (AHI; number of breath pauses or respiratory events per hour) by 32% whereas a 10% decrease in weight decreases the AHI by 26%.¹⁸

COMORBIDITIES

OSA is associated with a number of comorbid conditions including stroke, myocardial infarction, hypertension, hyperlipidemia, glucose intolerance, diabetes, arrhythmias including atrial fibrillation, pulmonary hypertension, congestive heart failure, and depression. Patients with moderate or severe OSA are at higher risk of these comorbid conditions.¹⁹

Patients with cardiovascular disease have a very high prevalence of OSA: hypertension (83% mild to 30% moderate to severe OSA), heart failure (55% to 12%), arrhythmias (50% to 20%), stroke (75% to 57%), and coronary heart disease (65% to 38%).²⁰ Increased awareness and early diagnosis of OSA is critical to reducing cardiovascular disease burden.

Sleep history

A sleep history starts with determining the patient’s total sleep time, based on time to bed, time to fall asleep, and time of wake up, including any difficulty falling asleep, staying asleep, or daytime naps.

Symptoms. Daytime naps generally indicate a sleep deficit or sleep that is not refreshing. A review of sleep and daytime symptoms associated with OSA (Table 1) helps determine if excessive daytime sleepiness or unrefreshing sleep is out of proportion with the amount of sleep the patient is getting at night.

Some patients with OSA may have memory or concentration issues or feel like they have attention deficit disorder. In fact some patients are diagnosed with attention deficit disorder because of their insufficient sleep or unrefreshing sleep.

Drowsy driving is a special concern in patients with untreated OSA and sleep deprivation. Many patients have drowsy driving episodes or difficulty staying awake during long-distance driving. Caffeine use is also important information as excessive caffeine may be used to combat sleepiness during the day.

The Epworth Sleepiness Scale is a clinical screening tool that presents 8 situations for patients to consider and indicate their level of sleepiness and likelihood of falling asleep (never = 0; slight = 1; moderate = 2, high = 3).^21,22 A total score ≥ 10 is considered abnormal in that the patient is excessively sleepy compared with most people.

Risk factors and comorbid conditions. OSA risk factors and comorbidities, including a BMI obesity assessment, should be reviewed with patients. Nasal congestion or mouth breathing especially at night could be due to airway obstruction increasing the risk of OSA. Family history of OSA, tobacco, alcohol use, other medical conditions, and medications should also be discussed.

Physical examination

• Neck circumference greater than 17 inches for men or greater than 16 inches for women
• BMI greater than 30
• Friedman class tongue position class 3 or greater (Figure 1)
• Mouth features (present/enlarged tonsils, macroglossia, jaw misalignment)
• Nasal abnormalities (turbinate hypertrophy, deviated septum).⁵

Patients with Friedman palate positions class 3 and 4 have a higher risk of OSA due to airway crowding during sleep when the airway naturally collapses a little and is even more restricted.

Narrow airways or oropharyngeal crowding can also be due to a swollen, enlarged, or elongated uvula; present or enlarged tonsils; or lateral wall narrowing. Alone or in combination, these features can contribute to airway obstruction.

Other signs in the mouth suggestive of obstruction are macroglossia (enlarged tongue) and tongue ridging. Tongue ridging or scalloping impressions typically occur during sleep and are caused by the tongue moving forward to open the airway and pressing against the teeth.

Retrognathia (lower jaw offset behind upper jaw) can narrow the airway and increase the risk of OSA as can a high arch palate, overbite (upper teeth forward), or overjet (upper teeth over the top of lower teeth).

A nasal examination for nasal valve collapse (ie, nostril collapses with inhalation), deviated septum, and inferior turbinate hypertrophy impart an increased risk of OSA.

Screening tools

In addition to the Epworth Sleepiness Scale, the STOP-BANG questionnaire can help determine if a patient should be tested further for OSA. The STOP-BANG questionnaire consists of 8 yes-no questions where more than 2 yes responses indicate the patient is at higher risk for moderate to severe OSA (93% sensitivity): Snore, Tired, Observed stopped breathing, high blood Pressure, BMI > 35 kg/m², Age > 50, Neck > 15.75 inches, Gender = male).²³

Polysomnography

Home sleep apnea test

HSATs record 4 to 7 parameters including airflow (thermal and nasal pressure), effort (inductive ple­thysmography), and oximetry. No electroencephalogram is used, so sleep is not recorded; it is assumed the patient is sleeping for the duration of the test. As such, respiratory events are based on oxygen desaturations and reduced airflow and pressure as well as chest and abdomen effort. The raw data are edited and manually scored and reviewed by a sleep specialist.²⁵

Although the HSAT is convenient for many patients, it underestimates the severity of sleep-related breathing disorders. HSAT is intended to confirm OSA in patients with a high likelihood of OSA based on their sleep history.²⁶ It is ideally employed for adult patients with no major medical problems or other sleep problems who are at high risk for moderate to severe OSA based on the STOP-BANG questionnaire or those with daytime sleepiness and 2 of the 3 symptoms of snoring, witnessed apnea, or hypertension.²⁷

A negative or inconclusive HSAT warrants a PSG to ensure the patient does not have OSA. Use of HSAT is contraindicated in patients with

• Significant cardiopulmonary disease
• Potential weakness due to a neuro­muscular condition
• Awake hypoventilation or high risk for sleep-related hypoventilation (severe obesity)
• History of stroke
• Chronic opioid use
• Severe insomnia
• Symptoms of other significant sleep disorders
• Environmental/personal factors that would preclude adequate acquisition and interpretation of data (disruptions from children, pets, other factors).²⁷

DIAGNOSTIC CRITERIA

Respiratory events captured on a PSG or HSAT

The OSA diagnostic criteria are based on the occurrence of obstructive respiratory events recorded during sleep such as apneas, hypopneas, and respiratory event-related arousals.

Hypopneas. A hypopnea is a respiratory event resulting in reduced airflow. The America Association of Sleep Medicine’s preferred definition is a reduction in nasal pressure of at least 30% for 10 seconds or longer with 3% or greater oxygen desaturation or an electroencephalogram arousal. Another acceptable definition is at least 30% reduction in thoracoabdominal movement or airflow with 4% or greater oxygen desaturation, which is used by the Centers for Medicare and Medicaid Services and other insurers.^29,30 Hypopnea requires greater oxygen desaturation and is not dependent on arousals, which can sometimes make it more challenging to identify OSA (Figure 2).

Respiratory event-related arousals. Respiratory event-related arousals are respiratory events not meeting apnea or hypopnea criteria. They are measured as a sequence of breaths of 10 or more seconds with increasing respiratory effort or flattening of the nasal pressure waveform leading to arousal (Figure 2).²⁹ Respiratory event-related arousals are disruptive to sleep and have many of the same consequences as apneas and hypopneas.

Severity

SUMMARY

OSA results from airway collapse and obstruction during sleep, often causing arousal from sleep with or without oxygen desaturation. The prevalence of OSA is underestimated and it is underdiagnosed despite known risk factors and comorbid conditions. Screening for OSA with a sleep history, simple upper airway examination, and quick validated screening tool like the STOP-BANG or Epworth Sleepiness Scale aid in identifying the need for testing for OSA. A laboratory sleep study with a PSG can confirm the diagnosis and severity of OSA. HSATs are available to confirm the diagnosis of OSA in patients at high risk for moderate to severe OSA.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

SLEEP AND CARDIOVASCULAR PHYSIOLOGY

Wakefullness and sleep, the latter comprised of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, comprise our primary states of being. Sleep states oscillate between NREM and REM sleep. The first and shortest period of REM sleep typically occurs 90 to 120 minutes into the sleep cycle. Most REM sleep, including the longest period of REM sleep, occurs during the latter part of the sleep cycle.

With these sleep state changes, physiologic changes also occur, such as reduced heart rate and blood pressure because of enhanced parasympathetic tone. During REM sleep, there are also intermittent sympathetic nervous system surges. Other physiologic changes include a regular respiratory rate during NREM sleep and an irregular respiratory rate during REM sleep. Body temperature is normal during NREM sleep and poikilothermic (ie, tends to flucuate) during REM sleep. Blood pressure is reduced 10% to 15% during sleep¹ and then rises, so that the highest blood pressure occurs in the morning. Data from 10 million users of activity-monitoring devices show that the heart rate changes during sleep.² The heart rate is decreased in those who get less than 7 hours of sleep, then increases with longer sleep duration in a U-shaped distribution.

Cardiovascular events are more likely to occur at certain times of day. Myocardial infarction is more likely in the morning, with a threefold increased risk within the first 3 hours of awakening that peaks around 9 AM.^3,4 Similar diurnal patterns have been observed with other cardiovascular conditions such as sudden cardiac death and ischemic episodes, with the highest risk during morning hours (6 to 9 AM).⁴

The reason for this morning predisposition for cardio­vascular events is unclear, but it is thought that perhaps the autonomic fluctuations that occur during REM sleep and the predominance of REM sleep in early morning may be a factor. Diurnal changes in blood pressure and cortisol levels may also contribute, as well as levels of systemic inflammatory and thrombotic markers such as plasminogen activator inhibitor 1.

Arrhythmias are also more likely to occur in a diurnal pattern. Atrial fibrillation (AF), particularly paroxysmal AF, is believed to be vagally mediated in 10% to 25% of patients.⁵ Therefore, for those who are predisposed, sleep may represent a period of increased risk for AF. In a study of individuals 60 years and older, the maximum duration and peak frequency of AF occurred from midnight to 2 AM.⁵

Recent studies have found that REM-related obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. Experimental models show that REM sleep may increase the risk for compromised coronary blood flow.⁶ Increased heart rate corresponds to reduced coronary blood flow and thus, to decreased coronary perfusion time and less time for relaxation of the heart, increasing the risk for coronary artery disease, thrombosis, and ischemia.

SLEEP APNEA PATHOPHYSIOLOGY

The normal physiology of the sleep-heart inter­action is disrupted by sleep apnea. OSA is defined as episodes of complete or partial airway obstruction that occur during sleep with thoraco­abdominal effort. Central sleep apnea (CSA) is the cessation of breathing with no thoracoabdominal effort. The pathophysiology of the sleep-heart interaction varies for OSA and CSA.

Obstructive sleep apnea

OSA is a nocturnal physiologic stressor that is highly prevalent and underrecognized. It affects approximately 17% of the adult population, and the prevalence is increasing with the obesity epidemic. Nearly 1 in 15 individuals is estimated to be affected by at least moderate OSA.^7,8 OSA is underdiagnosed particularly in minority populations.⁹ Data from the 2015 Multi-Ethnic Study of Atherosclerosis (MESA) showed undiagnosed moderate to severe sleep apnea in 84% to 93% of individuals,⁹ similar to an estimated 85% of undiagnosed cases in 2002.¹⁰

OSA is highly prevalent in individuals with underlying coronary disease^11–13 and in those with cardiovascular risk factors such as diabetes, hypertension, and heart failure. The prevalence of OSA in patients with cardiovascular disease ranges from 30% (hypertension) to 60% (stroke or transient ischemic attack, arrhythmia, end-stage renal disease).¹⁴

The alterations in sympathetic activation that occur during sleep in patients with OSA persist during wakefulness. Microneurographic recording of sympathetic nerve activity in the peroneal nerve reveal that the rate of sympathetic bursts doubles and the amplitude is greater in individuals with OSA compared with a control group.¹⁵

Sympathetic nerve activity, blood pressure, and heart rate were shown to increase during REM sleep in individuals with OSA on continuous positive airway pressure (CPAP) during an induced apneic event (pressure reduction from 8 cm to 6 cm of water).¹⁵

During OSA episodes, there is an increased cardiac load. Impaired diastolic function and atrial and aortic enlargement, and in particular, the thin-walled atria are very susceptible to the intra­thoracic pressure swings caused by OSA. Physiologic changes with OSA from pressure changes in the chest result in shift of the intraventricular septum, causing a reduction in cardiac output.¹⁶ With the lowering of oxygen during episodes of apnea, constriction of the pulmonary vasculature leads to elevation of pressure in the pulmonary vasculature reflected by the increase in mean pulmonary arterial pressures.¹⁷

Other studies have shown that OSA increases upregulation of markers of systemic inflammation and prothrombotic markers, the very markers that can increase cardiovascular or atherogenic risk.^18–22 One example is the soluble interleukin 6 receptor, shown to be elevated in the morning relative to sleep apnea compared with the evening.²⁰ Other biomarkers observed to be associated with sleep apnea include markers of prothrombotic potentials such as plasminogen activator inhibitor 1.¹⁹ Oxidative stress occurs because intermittent bouts of lower oxygen can lead to oxidation of serum proteins and lipids. Endothelial dysfunction has been observed as well as insulin resistance and dyslipidemia.²³ Taken together, these are pathways that lead to atherogenesis and increased cardiovascular risk.

Central sleep apnea

CSA episodes are the cessation of breathing without thoracoabdominal effort, in contrast to the persistence of thoracoabdominal effort in OSA. CSA is characterized by breathing instability with highly sensitive chemoresponses and prolonged circulation time.²⁴ This can be physiologic in some cases, as when it occurs after a very large breath or sigh and then a central apnea event occurs after the sigh. The alterations in oxygen and CO₂ and the stretch of the receptors in the alveoli of the lungs initiate the Hering-Breuer inhalation reflex.

Pathophysiology of CSA

Complex pathways of medullary and aortic receptor chemosensitivity are at the root of the pathophysiology of CSA.²⁴ With CSA there is often a relative state of hypocapnia at baseline. During sleep, there is reduction in drive, thus chemo­sensitivity can be activated so that central apnea episodes can ensue as a result of alterations in CO₂ (ie, hypocapnia). Another factor that can contribute to the pathophysiology of CSA is arousal from sleep that can reduce CO₂ levels and therefore perpetuate central events.

The concept of loop gain is used to understand the pathophysiology of CSA. Loop gain is a measure of the relative stability of a ventilation system and indicates the likelihood of an individual to have periodic breathing. It is calculated by the response to a disturbance divided by the disturbance itself.²⁵ With a high loop gain, there is a more pronounced or exuberant response to the disturbance, indicating more instability in the system and increasing the tendency for irregular breathing and CSA episodes.

Hunter-Cheyne-Stokes respiration occurs with CSA and is characterized by cyclical crescendo-decrescendo respiratory effort that occurs during wakefulness and sleep without upper-airway obstruction.^26,27 Unlike OSA, which is worse during REM sleep, Hunter-Cheyne-Stokes breathing in CSA is typically worse in NREM sleep, during N1 and N2 in particular.

Both OSA and CSA are prevalent in patients with heart failure and may be associated with the progression of heart failure. CSA often occurs in patients with heart failure. The pathophysiology is multi­factorial, including pulmonary congestion that results in stretch of the J receptors in the alveoli, prolonged circulation time, and increased chemosensitivity.

Complex pathways in the neuroaxis or somnogenic biomarkers of inflammation or both may be implicated in the paradoxical lack of subjective sleepiness in the presence of increased objective measures of sleepiness in systolic heart failure. One study found a relationship with one biomarker of inflammation and oxidative stress as it relates to objective symptoms of sleepiness but not subjective symptoms of sleepiness.²⁸

Another contributing factor in the relationship between OSA and CSA in heart failure has also been described related to rostral shifts in fluid to the neck and to the pulmonary receptors in the alveoli of the lungs.²⁹ These rostral shifts in fluids may contribute to sleep apnea with parapharyngeal edema leading to OSA and pulmonary congestion leading to CSA.

Sleep apnea is associated with increased post-discharge mortality and hospitalization readmissions in the setting of acute heart failure.³⁰ Mortality analysis of 1,096 patients admitted for decompensated heart failure found CSA and OSA were independently associated with mortality in patients compared with patients with no or minimal sleep-disordered breathing.³⁰

CSA has also been shown to be a predictor of readmission in patients admitted for heart failure exacerbations.³¹ Targeting underlying CSA may reduce readmissions in those admitted with acute decompensated heart failure. While men were identified to be at increased risk of death relative to sleep-disordered breathing based on the initial results of the Sleep Heart Health Study, a subsequent epidemiologic substudy reflective of an older age group showed that OSA was more strongly associated with left ventricular mass index, risk of heart failure, or death in women compared with men.³²

Treatment

Standard therapy for treatment of OSA is CPAP. Adaptive servo-ventilation (ASV) and transvenous phrenic nerve stimulation are also available as treatment options in certain cases of CSA.

One of the first randomized controlled trials designed to assess the impact of CSA treatment on survival in patients with heart failure initially favored the control group then later the CPAP group and was terminated early based on stopping rules.^33,34 While adherence to therapy was suboptimal at an average of 3.6 hours, post hoc analysis showed that patients with CSA using CPAP with effective suppression of CSA had improved survival compared with patients who did not have effective suppression using CPAP.³⁴

ASV is mainly used for treatment of CSA. In ASV, positive airway pressure for ventilation support is provided and adjusts as apneic episodes are detected during sleep. The support provided adapts to the physiology of the patient and can deliver breaths and utilize anticyclic modes of ventilation to address crescendo-decrescendo breathing patterns observed in Hunter-Cheyne-Stokes respiration.

In the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) trial, 1,300 patients with systolic heart failure and predominantly CSA were randomized to receive ASV vs solely standard medical management.³⁵ The primary composite end point included all-cause mortality or unplanned admission or hospitalization for heart failure. No difference was found in the primary end point between the ASV and the control group; however, there was an unanticipated negative impact of ASV on cardiovascular outcomes in some secondary end points. Based on the secondary outcome of cardiovascular-specific mortality, clinicians were advised that ASV was contraindicated for the treatment of CSA in patients with symptomatic heart failure with a left ventricular ejection fraction less than 45%. The interpretation of this study was complicated by several methodologic limitations.³⁶

The Cardiovascular Improvements With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) randomized controlled trial also evaluated ASV compared with standard medical management in 126 patients with heart failure.³⁷ This trial was terminated early because of the results of the SERVE-HF trial. Compliance with therapy was suboptimal at an average of 2.7 hours per day. The composite end point did not differ between the 2 groups; however, this was likely because the study was underpowered and was terminated early. Subgroup analysis revealed that patients with heart failure with preserved ejection fraction may benefit from ASV; however, additional studies are needed to confirm these findings.

Therefore, although ASV is not indicated when there is predominantly CSA in patients with systolic heart failure, preliminary results support potential benefit in patients with OSA and preserved ejection fraction.

Another novel treatment for CSA is transvenous phrenic nerve stimulation. A device is implanted that stimulates the phrenic nerve to initiate breaths. The initial study of trans­venous phrenic nerve stimulation reported a significant reduction in the number of episodes of central apnea per hour of sleep.^38,39 The apnea–hypopnea index improved overall and some types of obstructive apneic events were reduced with transvenous phrenic nerve stimulation.

A multicenter randomized control trial of trans­venous phrenic nerve stimulation found improvement in several sleep apnea indices, including central apnea, hypoxia, reduced arousals from sleep, and patient reported well-being.⁴⁰ Transvenous phrenic nerve stimulation holds promise as a novel therapy for central predominant sleep apnea not only in terms of improving the degree of central apnea and sleep-disordered breathing, but also in improving functional outcomes. Longitudinal and intereventional trial data are needed to clarify the impact of transvenous phrenic nerve stimulation on long-term cardiac outcomes.

SLEEP APNEA AND ATRIAL FIBRILLATION AND STROKE

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia. The number of Americans with AF is projected to increase from 2.3 million to more than 10 million by the year 2050.⁴¹ The increasing incidence and prevalence of AF is not fully explained by the aging population and established risk factors.⁴² Unrecognized sleep apnea, estimated to exist in 85% or more of the population, may partially account for the increasing incidence of AF.⁴³

There are 3 types of AF, which are thought to follow a continuum: paroxysmal AF is characterized by episodes that occur intermittently; persistent AF is characterized by episodes that last longer than 7 days; chronic or permanent AF is typically characterized by AF that is ongoing over many years.⁴⁴ As with sleep apnea, AF is often asymptomatic and is likely underdiagnosed.

Sleep apnea and AF share several risk factors. Obesity is a risk factor for both OSA and AF; however, a meta-analysis supported a stronger association of OSA and AF vs obesity and AF.⁴⁵ Increasing age is a risk factor for both OSA and AF.^46,47 Although white populations are at higher risk for AF, OSA is associated with a 58% increased risk of AF in African Americans.⁴⁸ Nocturnal hypoxia has been associated with increased risk of AF in Asians.⁴⁹

Experimental data continue to accrue providing biologic plausibility of the relationship between sleep apnea and AF. OSA contributes to structural and electrical remodeling of the heart with evidence supporting increased fibrosis and electrical remodeling in patients with OSA compared with a control group.⁵¹ Markers of structural remodeling, such as atrial size, electrical silence, and atrial voltage conduction velocity, are altered in OSA.⁵⁰

Data from the Sleep Heart Health Study show very strong associations between atrial and ventricular cardiac arrhythmias and sleep apnea with two- to fivefold higher odds of arrhythmias in patients with severe OSA compared with controls even after accounting for confounding factors such as obesity.⁵²

A multicenter, epidemiological study of older men showed that increasing severity of sleep apnea corresponds with an increased prevalence of AF and ventricular ectopy.⁵³ This graded dose-response relationship suggests a causal relationship between sleep apnea and AF and ventricular ectopy. There also appears to be an immediate influence of apneic events and hypopneic events as it relates to arrhythmia. A case-crossover study showed an associated 18-fold increased risk of nocturnal arrhythmia within 90 seconds of an apneic or hypopneic event.⁵⁴ This association was found with paroxysms of AF and with episodes of nonsustained ventricular tachycardia.

Data from a clinic-based cohort study show an association between AF and OSA.⁵⁵ Specifically, increased severity of sleep apnea was associated with an increased prevalence of AF. Increasing degree of hypoxia or oxygen-lowering was also associated with increased incidence of AF or newly identified AF identified over time.

Longitudinal examination of 2 epidemiologic studies, the Sleep Heart Health Study and Outcomes of Sleep Disorders Study in Older Men, found CSA to be predictive of AF with a two- to threefold higher odds of developing incident AF as it related to baseline CSA.⁵⁶ According to these data, CSA may pose a greater risk for development of AF than OSA.

With respect to AF after cardiac surgery, patients with sleep apnea and obesity appear to be at higher risk for developing AF as measured by the apnea–hypopnea index and oxygen desaturation index.⁵⁷

Treatment of sleep apnea may improve arrhythmic burden. Case-based studies have shown reduced burden and resolution of baseline arrhythmia with CPAP treatment for OSA as therapeutic pressure was achieved.⁵⁸ Another case-based study involved an individual with snoring and OSA and AF at baseline.⁵⁹ Several retrospective studies have shown that treatment of OSA after ablation and after cardio­version results in reduced recurrence of AF; however, large definitive clinical trials are lacking.

Stroke

Sleep apnea is a risk factor for stroke due to intermittent hypoxia-mediated elevation of oxidative stress and systemic inflammation, hypercoaguability, and impairment of cerebral autoregulation.⁶⁰ However, the relationship may be bidirectional in that stroke may be a risk factor for sleep apnea in the post-stroke period. The prevalence of sleep apnea post-stroke has been reported to be up to 70%. CSA can occur in up to 26% during the post-stroke phase.⁶¹ Data are inconsistent in terms of the location and size of stroke and the risk of sleep apnea, though cerebrovascular neuronal damage to the brainstem and cortical areas are evident.⁶² In one study, the incidence of stroke appeared to increase with the severity of sleep apnea.⁶³ These findings were more pronounced in men than in women; however, this study may not have captured the increased cardiovascular risk in postmenopausal women. The Outcomes of Sleep Disorders in Older Men study found that severe hypoxia increased the incidence of stroke, and that hypoxia may be a predictor of newly diagnosed stroke in older men.⁶⁴ Although definitive clinical trials are underway, post-hoc propensity-score matched analysis from the Sleep Apnea Cardiovascular Endpoints (SAVE) study showed a lower stroke risk in those adherent to CPAP compared with the control group (HR=0.56, 95% CI: 0.30-0.90).⁶⁵

The association between sleep apnea and coronary artery disease and cardiovascular mortality was considered in a Spanish study of 1,500 patients followed for 10 years, which reported that CPAP therapy reduced cardiac events in patients with OSA.⁶⁶ Patients with sleep apnea had an increased risk of fatal myocardial infarction or stroke. Survival of patients treated for sleep apnea approached that of patients without OSA.

In a study of a racially diverse cohort, an association of physician diagnosed sleep apnea with cardiovascular events and survival was identified.⁶⁷ Diagnosed sleep apnea was estimated to confer a two- to threefold increase in various cardiovascular outcomes and all-cause mortality.

Punjabi NM, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6(8):e1000132.

The effect of treatment for sleep apnea on cardiovascular outcomes was the focus of a recent randomized controlled trial of nearly 3,000 participants with a mean follow-up of 4 years.65 Use of CPAP compared with usual care found no difference in cardiovascular outcomes. However, secondary analysis revealed a possible benefit of a lower risk of stroke with use of CPAP therapy. Several factors should be considered in interpreting these findings: ie, low adherence with CPAP therapy (3 hours), whether the study was sufficiently powered to detect a change in cardiovascular outcomes, and if the duration of follow-up was adequate. In terms of patient demographics and study generalizability, the study did not include patients with severe sleep apnea and hypoxia, and most participants were men, of Asian descent, with a mean body mass index of 28 kg/m2, and low levels of sleepiness at baseline.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.

Obstructive sleep apnea (OSA) is a serious condition that impacts quality of life and causes drowsy driving and depression. Research also reveals an interrelationship between OSA and metabolic disease and an association between OSA and cognitive impairment.

The diagnostic criteria of OSA are based on the number of apneic or hypopneic episodes per hour of sleep, called the apnea–hypopnea index (AHI) as recorded during sleep testing. Diagnosis of OSA is warranted if the AHI is 15 or more per hour or if the AHI is 5 or more per hour with 1 or more of the following features: sleepiness; nonrestorative sleep; fatigue or insomnia; waking up with breath-holding spells, gasping, or choking; snoring or breathing interruptions; or a coexisting diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type II diabetes.¹

Many patients with an AHI less than 15 may also have OSA, given the number of coexisting medical conditions included in the OSA diagnostic criteria. Heart conditions such as coronary artery disease, atrial fibrillation, and congestive heart failure encompassed in the OSA diagnostic criteria have increased awareness of the link between OSA and heart health. Less well-known, and the subject of this review, are the negative consequences of OSA, particularly poor quality of life, drowsy driving, depression, metabolic disease, and cognitive impairment.

QUALITY OF LIFE

Reduced quality of life is the most fundamental patient-reported outcome of OSA. OSA is associated with excessive daytime sleepiness, inattention, and fatigue, which increase the risk of accidents and medical disability. These quality-of-life impairments are often the main reason patients seek medical care for sleep disorders.² Improved quality of life is a central goal of OSA treatment and is the best indicator of the effectiveness of treatment.³ Sleep health and its effect on quality of life is an area of focus of Healthy People 2020 (healthypeople.gov).

The American Academy of Sleep Medicine identified quality of life, along with detection of disease and cardiovascular consequences, as an outcome measure for assessing the quality of care for adults with OSA.² The assessment of quality of life for patients with OSA is a 4-part process: use evidence-based therapy, monitor the therapy, assess symptoms with a validated tool such as Epworth Sleepiness Scale, and assess the incidence of motor vehicle accidents. Information from these 4 processes can inform changes in a patient’s quality of life.

Treatment for OSA has been shown to improve quality of life. A study of 2,027 patients with OSA evaluated therapy adherence relative to mean Functional Outcomes of Sleep Questionnaire and European Quality of Life-5D scores.⁴ In patients with the most impaired quality of life, those adherent to positive airway pressure (PAP) therapy had improved quality of life as measured by these scores.

With respect to sleepiness, a systematic review of continuous PAP (CPAP) in patients with OSA found a 2.7-point reduction (mean difference; 95% confidence interval 3.45–1.96) in the Epworth Sleepiness Scale in patients using CPAP compared with the control group.⁵ Treatment of OSA improves patient quality of life and symptoms such as sleepiness.

DROWSY DRIVING

Drowsy driving by people with OSA can lead to motor vehicle accidents, which result in economic and health burdens.^6,7 National Center for Statistics and Analysis data reveal that of 6 million motor vehicle accidents (5-year average, 2005–2009), 1.4% involve drowsy driving and 2.5% of fatal crashes involve drowsy driving.⁸ Among noncommercial drivers, untreated OSA increases the risk of motor vehicle accidents 3- to 13-fold.⁹ The odds ratio of traffic accidents in drivers with untreated OSA is 6 times greater than in the general population.⁷

In a study of men and women in the general population (N = 913), individuals with moderate to severe OSA (AHI > 15) were more likely to have multiple motor vehicle accidents in the course of 5 years (odds ratio = 7.3) compared with those with no sleep-disordered breathing.¹⁰ The association between OSA and motor vehicle accidents is independent of sleepiness, and drivers with OSA may not perceive performance impairment.

There are 2 main reasons OSA increases the risk and incidence of motor vehicle accidents. OSA causes changes in attention and vigilance resulting from sleep deprivation and fragmentation. OSA also affects global cognition function, which may be due to intermittent hypoxia attributable to OSA.²

Treatment for OSA is effective in reducing the incidence of motor vehicle accidents. One study found the risk of motor vehicle accidents was eliminated with the use of CPAP treatment in patients with OSA.¹¹ A recent study of nearly 2,000 patients with OSA found a reduction in self-reported near-accidents from 14% before PAP therapy to 5.3% after starting PAP therapy.¹²

Estimates of the prevalence of depression in patients with OSA range from 5% to 63%.^13,14 One year after patients were diagnosed with OSA, the incidence of depression per 1,000 person-years was 18% compared with 8% in a group without OSA.¹⁴ Women with OSA reportedly have a higher risk of depression (adjusted hazard ratio [HR] 2.7) than men (HR 1.81) at 1-year follow-up.¹⁴ In the same study, with respect to age, there was no significant relationship noted between OSA and patients over age 64.

A one-level increase in the severity of OSA (ie, from minimal to mild) is associated with a nearly twofold increase in the adjusted odds for depression.¹⁵ On the other hand, studies have also found that patients on antidepressants may have an increased risk of OSA.¹⁶

Several potential mechanisms have been proposed to explain the link between depression and OSA.¹³ Poor-quality sleep, frequent arousal, and fragmentation of sleep in OSA may lead to frontal lobe emotional modulation changes. Intermittent hypoxia in OSA may result in neuronal injury and disruption of noradrenergic and dopaminergic pathways. Pro-inflammatory substances such as interleukin 6 and interleukin 1 are increased in OSA and depression and are mediators between both conditions. Neurotransmitters may be affected by a disrupted sleep-wake cycle. And serotonin, which may be impeded in depression, could influence the upper-airway dilator motor neurons.

Treatment of OSA improves symptoms of depression as measured by the Patient Health Questionnaire (PHQ-9). After 3 months of compliance with CPAP therapy, mean PHQ-9 scores decreased from 11.3 to 2.7 in a study of 228 patients with OSA.¹⁷ A study of 1,981 patients with sleep-disordered breathing found improved PHQ-9 scores in patients compliant with CPAP therapy and a greater improvement in patients with a baseline PHQ-9 higher than 10 (moderate severity).¹⁸

METABOLIC SYNDROME

OSA is associated with metabolic disorders, including metabolic syndrome, though the causality between these 2 conditions is yet to be illuminated. Metabolic syndrome is a term used when an individual has 3 or more of the following features or conditions:

• Waist circumference greater than 40 inches (men), greater than 35 inches (women)
• Triglycerides 150 mg/dL or greater or treatment for hypertriglyceridemia
• High-density lipoprotein cholesterol less than 40 mg/dL (men), less than 50 mg/dL (women), or treatment for cholesterol
• Blood pressure 130/85 mm Hg or greater, or treatment for hypertension
• Fasting blood glucose 100 mg/dL or greater, or treatment for hyperglycemia.¹⁹

Metabolic syndrome increases an individual’s risk of diabetes and cardiovascular disease and overall mortality. Like OSA, the prevalence of metabolic syndrome increases with age in both men and women.^20,21 The risk of metabolic syndrome is greater with more severe OSA. The Wisconsin Sleep Cohort (N = 546) reported an odds ratio for having metabolic syndrome of 2.5 for patients with mild OSA and 2.2 for patients with moderate or severe OSA.²² A meta-analysis also found a 2.4 times higher odds of metabolic syndrome in patients with mild OSA, but a 3.5 times higher odds of metabolic syndrome in patients with moderate to severe OSA compared with the control group.²³

Patients with both OSA and metabolic syndrome are said to have syndrome Z²⁴ and are at increased risk of cardiovascular morbidity and mortality.²⁵ Syndrome Z imparts a higher risk of atherogenic burden and prevalence of atheroma compared with patients with either condition alone.²⁶ In comparing patients with metabolic syndrome with and without OSA, those with OSA had increased atherosclerotic burden as measured by intima-media thickness and carotid femoral pulse-wave velocity.²⁷ Syndrome Z is also linked to intracoronary stenosis related to changes in cardiac morphology²⁸ and is associated with left ventricular hypertrophy and diastolic dysfunction.²⁹

OSA and hypertension

Hypertension is one of the conditions encompassed in metabolic syndrome. Several studies report increased risk and incidence of hypertension in patients with OSA. In a community-based study of 6,123 individuals age 40 and older, sleep-disordered breathing was associated with hypertension, and the odds ratio of hypertension was greater in individuals with more severe sleep apnea.³⁰ Similarly, a landmark prospective, population-based study of 709 individuals over 4 years reported a dose-response relationship between patients with OSA and newly diagnosed hypertension independent of confounding factors.³¹ Patients with moderate to severe OSA had an odds ratio of 2.89 of developing hypertension after adjusting for confounding variables.

A study of 1,889 individuals followed for 12 years found a dose-response relationship based on OSA severity for developing hypertension.³² This study also assessed the incidence of hypertension based on CPAP use. Patients with poor adherence to CPAP use had an 80% increased incidence of hypertension, whereas patients adhering to CPAP use had a 30% decrease in the incidence of hypertension.

Resistant hypertension (ie, uncontrolled hypertension despite use of 3 or more antihypertensive and diuretic medications) has been shown to be highly prevalent (85%) in patients with severe OSA.³³ An analysis of patients at increased risk of cardiovascular disease and untreated severe OSA was associated with a 4 times higher risk of elevated blood pressure despite intensive medical therapy.³⁴

Mechanisms implicated in altering metabolic regulation in OSA include intermittent hypoxia, sleep fragmentation and glucose homeostasis, and obesity. Intermittent hypoxia from OSA results in sympathetic nervous system activation that affects the pancreas, skeletal muscle, liver, and fat cells resulting in altered insulin secretion, lipid-bile synthesis, glucose metabolism, and lipoprotein metabolism.³⁵

Sleep fragmentation is a cardinal feature of OSA and the resulting suppression of sleep may alter insulin sensitivity. Studies have implicated disruptions to slow-wave sleep specifically, as well as disruption of any stage of sleep in reduced insulin sensitivity.^35,36 In addition to decreased insulin sensitivity, sleep fragmentation also increases morning cortisol levels and increases sympathetic nervous system activation.³⁷

Obesity and OSA share a pathway imparting increased cardiometabolic risk.³⁸ Fat tissue causes higher systemic inflammation and inflammatory markers. A recent report describes a bidirectional relationship between metabolic syndrome and OSA.³⁹ While OSA increases the risk for metabolic syndrome, metabolic syndrome by virtue of body mass index with changes in mechanical load and narrow airway and physiology can predispose for OSA.

Effect of treatment for OSA on metabolic syndrome

Several studies have evaluated the effect of CPAP treatment for OSA on metabolic syndrome overall, as well as the specific conditions that comprise metabolic syndrome. In evaluating CPAP use and metabolic syndrome overall, studies have found a reduced prevalence of metabolic syndrome,^40,41 CPAP benefit only in complying patients,⁴² and a reduction in oxidative stress with a single-night use of CPAP.⁴³

With respect to insulin sensitivity, a study of 40 men with moderate OSA using CPAP therapy (mean use 5 hours) reported an increase in the insulin sensitivity index after 2 days, and a further increase after 3 months.⁴⁴ Another study found no improvement in insulin resistance in severe OSA.⁴⁵ A meta-analysis reported improved insulin resistance with CPAP,⁴⁶ although a recent meta-analysis assessing hemoglobin A_1c level, fasting insulin level, and fasting glucose did not show improvement in these parameters. Large-scale clinical trials with longer treatment duration and better CPAP compliance are warranted.⁴⁷

Weight loss has been shown to reduce the AHI and other parameters related to sleep apnea such as oxygen desaturation index in patients with obesity and diabetes.⁵⁹ Weight loss combined with CPAP compared with CPAP or weight loss alone showed an incremental benefit in improving glucose parameters, triglycerides, and possibly systolic blood pressure and triglycerides.⁶⁰

Data suggest that OSA is linked with cognitive impairment, may advance cognitive decline, and is a bidirectional relationship. Women with OSA were reportedly more likely to develop mild cognitive impairment compared with women without OSA.⁶¹ An elevated oxygen desaturation index and a high percentage of time spent with hypoxia was associated with increased risk of developing mild cognitive impairment and dementia.

OSA was found to be an independent risk factor for cerebral white matter changes in middle-age and older individuals. Moderate to severe OSA imparted a 2 times higher risk of cerebral white matter changes compared with individuals without OSA.⁶² Another study of 20 patients with severe OSA compared with 40 healthy volunteers found diffusion imaging consistent with impaired fibrin integrity in those with OSA, indicative of white matter microstructure damage, and the impairment was associated with increased disease severity and higher systemic inflammation.⁶³

Individuals with hypoxia for a high percentage of time during sleep had a 4 times higher odds of cerebral microinfarcts.⁶⁴ Cognitive scores decreased less in men. Men typically have more time in slow-wave sleep, suggesting that slow-wave sleep may be protective against cognitive decline. Mild cognitive impairment and Alzheimer disease were found more likely to develop and occur at an earlier age in individuals with sleep-disordered breathing compared with individuals without sleep-disordered breathing.⁶⁵

OSA was also associated with increased serum amyloid beta levels in a study of 45 cognitively normal patients with OSA compared with 49 age- and sex-matched control patients. Increased amyloid beta levels correlated with increasing severity of sleep apnea as measured by the AHI.⁶⁶

Mechanism linking OSA and cognition

One possible mechanism linking sleep quality and cognitive impairment or Alzheimer disease is the role of unfragmented sleep in attenuating the apolipo­protein E e4 allele on the incidence of Alzheimer disease.⁶⁷ Beta amyloid is released during synaptic activity. Neuronal and synaptic activity decreases during sleep, and disrupted sleep could increase beta amyloid release.⁶⁸ Sleep has been found to enhance the clearance of beta amyloid peptide from the brain interstitial fluid in a mice model.⁶⁹

Recent data point toward the bidirectional relationship between the sleep and Alzheimer disease in that excessive and prolonged neuronal activity in the absence of appropriately structured sleep may be the reason for both Alzheimer disease and OSA.^70,71

Effect of treatment for OSA on cognition

White matter integrity in 15 patients with OSA before and after treatment with CPAP was compared with 15 matched controls. Over 12 months, there was a nearly complete reversal of white matter abnormalities in patients on CPAP therapy.⁷² Improvement in memory, attention, and executive function paralleled the changes in white matter after the treatment.

CONCLUSION

OSA is a serious condition with far-reaching consequences associated with impaired quality of life, depressive symptoms, drowsy driving, metabolic disease, and cognitive decline. Treatment of OSA improves many of these health consequences, emphasizing the need for OSA screening. Large randomized studies are needed to assess the efficacy of CPAP on metabolic outcomes, including insulin sensitivity and glucose tolerance, in reducing disease burden. Study of the endophenotypes of patients with OSA is needed to define and target the mechanisms of OSA-induced adverse health outcomes and perhaps lead to personalized care for patients with OSA.