Central Sleep Apnea (CSA)

Epidemiology

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Risk Factors

  • Acromegaly (see Acromegaly, [[Acromegaly]])
  • Age >65 y/o
    • Epidemiology: unclear if this is related to increased prevalence of comorbid disease (congestive heart failure, cerebrovascular disease, and atrial fibrillation) or sleep state oscillation
  • Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Male Sex
    • Physiology: males have a higher apneic threshold (requires the PaCO2 to be decreased a smaller amount to induce central apnea) -> greater susceptibility to CSA
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Epidemiology: both obstructive sleep apnea and central sleep apnea are prevalent in CHF
      • CSA is Most Commonly Observed in Male CHF Patients Older than 60 y/o with Atrial Fibrillation and/or Daytime Hypocapnia (pCO2 <38 mm Hg)
  • Stroke (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
    • Epidemiology: central sleep apnea is common in the acute period following stroke
    • Prognosis: improves over time in most cases
  • Opiates
    • Most Commonly Implicated Agents

Etiology

Central Sleep Apnea Syndromes (Associated with Normal Nocturnal pCO2)

  • Primary Central Sleep Apnea
    • Physiology: unknown, may be related to failure of expiratory to inspiratory switch influenced by chemoreceptors and chest wall/lung volume mechanoreceptors
  • Central Sleep Apnea Due to Cheyne-Stokes Respiration (CSR)
    • Epidemiology: predominantly seen in congestive heart failure (CHF)
    • Physiology: low cardiac output, resulting in high loop gain with feedback delay
      • Enhanced ventilatory drive with narrowed apneic threshold -> cyclic over and undershoot of ventilation with sleep state changes
  • Central Sleep Apnea Due to High-Altitude Periodic Breathing (see High Altitude, [[High Altitude]])
    • Physiology: decreased fractional oxygen concentration -> hypoxemia, resulting in high loop gain
      • Enhanced ventilatory drive with narrowed apneic threshold -> cyclic over and undershoot of ventilation with sleep state changes
  • Central Sleep Apnea Due to Opiates (see Opiates, [[Opiates]])
    • Physiology: opioid effects on the pre-Bötzinger complex resulting in erratic behavior of the ventilatory control center -> variable loop gain
    • Most Commonly Implicated Agents
      • Methadone (see Methadone, [[Methadone]])
        • Studies report that 30% of patients on stable methadone have central sleep apnea (a minority of which can be explained by the blood methadone concentration) (Chest, 2005) [MEDLINE]
        • Studies report an association between chronic methadone use and sleep-disordered breathing, with obstructive sleep apnea being observed more commonly than central sleep apnea (Drug Alcohol Depend, 2010) [MEDLINE]
  • Treatment-Emergent Central Sleep Apnea (Complex Sleep Apnea) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]]): refers to the development of central sleep following the application of CPAP or a dental appliance
    • History: recently added to the International Classification of Sleep Disorders, 3rd ed (Chest, 2014) [MEDLINE]
    • Epidemiology: these central events cannot be attributed to another identifiable comorbidity such as Cheyne-Stokes breathing or use of opiates
    • Mechanism: may be related to hypocapnia or mask leak (J Clin Sleep Med, 2013) [MEDLINE]
    • Clinical
      • Usually Observed When the Patient Has Frequent Arousals from Sleep
      • Occurs After the Obstructive Events are Controlled During NREM Sleep

Sleep-Related Hypoventilation Disorders (Associated with Elevated Nocturnal pCO2)

Ventilatory Control Abnormalities

  • Congenital Central Alveolar Hypoventilation Syndrome (CCAHS)
    • Physiology: blunted loop gain
      • Mutations in the PHOX2B gene, resulting in altered ventilatory control
  • Idiopathic Sleep-Related Non-Obstructive Alveolar Hypoventilation
    • Physiology: low loop gain

Neuromuscular Disease

  • Cervical Spinal Cord Injury Spinal Cord Injury, [[Spinal Cord Injury]])
    • Physiology: inability to translate ventilatory center output into appropriate action by neuromuscular apparatus, blunted ventilatory control blunted -> low loop gain
  • Myotonic Dystrophy (see Myotonic Dystrophy, [[Myotonic Dystrophy]])
    • Physiology: inability to translate ventilatory center output into appropriate action by neuromuscular apparatus, blunted ventilatory control blunted -> low loop gain
  • Spinal Muscular Atrophy (SMA) (see Spinal Muscular Atrophy, [[Spinal Muscular Atrophy]])
    • Physiology: inability to translate ventilatory center output into appropriate action by neuromuscular apparatus, blunted ventilatory control blunted -> low loop gain

Chest Wall Disease

  • Kyphoscoliosis (see Kyphoscoliosis, [[Kyphoscoliosis]])
    • Physiology: skeletal rigidity with increased work of breathing -> blunted intended response to carbon dioxide -> low loop gain
      • Over time, ventilatory control center undergoes adaptation, decreasing its responsivness to carbon dioxide
  • Obesity Hypoventilation Syndrome (OHS) (see Obesity Hypoventilation Syndrome, [[Obesity Hypoventilation Syndrome]])
    • Physiology: excessive load from adipose tissue with increased work of breathing -> blunted intended response to carbon dioxide -> low loop gain
      • Over time, ventilatory control center undergoes adaptation, decreasing its responsivness to carbon dioxide
  • Post-Thoracoplasty
    • Physiology: skeletal rigidity with increased work of breathing -> blunted intended response to carbon dioxide -> low loop gain
      • Over time, ventilatory control center undergoes adaptation, decreasing its responsivness to carbon dioxide

Lung Disease

  • Chronic Obstructive Pulmonary Disease (COPD) (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])
    • Physiology: underlying lung disease with decreased mechanical effectiveness of ventilation -> variable loop gain
      • Over time, ventilatory control center undergoes adaptation, decreasing its responsivness to carbon dioxide
  • Advanced Restrictive Lung Disease
    • Associated Diseases
    • Physiology: underlying lung disease with decreased mechanical effectiveness of ventilation -> variable loop gain
      • Over time, ventilatory drive remains high but its effectiveness is decreased by gas exchange abnormalities associated with pulmonary parenchymal damag

Physiology

General Concepts

  • Loop Gain: response of the ventilatory control system to a disturbance in ventilation
    • High Loop Gain: rapid but often unstable response to perturbations in ventilation (with alternating overshoot and undershoot)
    • Low Loop Gain: slow or incomplete response to perturbations in ventilation

Diagnosis

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Daytime Hypercapnia: seen in disorders with defects in chronic hypoventilation syndromes
  • Daytime Normocapnia/Hypocapnia (with Alkalemic pH): seen in disorders with fluctuations in respiratory drive (especially CHF, high-altitude-associated cases)
    • These disorders also manifest nocturnal hypocapnia, which may induce CSA

Polysomnography (see Polysomnography, [[Polysomnography]])

  • Central sleep apneas
  • Esophageal balloon measurement of negative pleural pressure swings may be necessary in some cases
  • Distribution in patients with defects in respiratory control/ muscle function: apneas seen across all sleep stages (more prolonged in REM), associated with resultant desaturations and hypercapnia
  • Distribution in patients with transient fluctuations in respiratory drive: apneas seen mostly in light sleep with intermittent arousals (associated with hyperpnea), associated with at most mild desaturations and mild hypocapnia (which further inhibits respiratory drive)

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • Usually normal
  • MIP/MEP: normal

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Polycythemia: may occur (if chronic daytime hypoxemia is present)

Electromyogram (EMG)/Nerve Conduction Velocity (NCV) (see Electromyogram-Nerve Conduction Velocity, [[Electromyogram-Nerve Conduction Velocity]])

  • Normal

Clinical/Diagnostic Criteria (International Classification of Sleep Disorders, 3rd Edition; Chest, 2014) [MEDLINE]

Primary Central Sleep Apnea

  • Polysomnographic Criteria
    • Study with ≥5 Central Apneas and/or Central Hypopneas Per Hour of Sleep
    • Number of Central Apneas and/or Central Hypopneas is >50% of the Total Number of Apneas and Hypopneas
    • Absence of Cheyne-Stokes Respiration
  • Patient Reports Sleepiness, Awakening with Shortness of Breath, Snoring, Witnessed Apneas, or Insomnia (Difficulty Initiating or Maintaining Sleep, Frequent Awakenings, or Nonrestorative Sleep)
  • Absence of Daytime or Nocturnal Hypoventilation
  • Disorder is Not Better Explained by Another Current Sleep Disorder, Medical or Neurologic Disorder, Medication Use, or Substance Use Disorder

Central Sleep Apnea with Cheyne-Stokes Respiration (CSR)

  • Polysomnographic Criteria
    • Study with ≥5 Central Apneas and/or Central Hypopneas Per Hour of Sleep
    • Number of Central Apneas and/or Central Hypopneas is >50% of the Total Number of Apneas and Hypopneas
    • Presence of at Least 3 Consecutive Central Apneas and/or Central Hypopneas Separated by Crescendo-Decrescendo Breathing with a Cycle Length of at Least 40 sec (ie, Cheyne-Stokes Breathing Pattern)
  • Patient Reports Sleepiness, Awakening with Shortness of Breath, Snoring, Witnessed Apneas, or Insomnia (Difficulty Initiating or Maintaining Sleep, Frequent Awakenings, or Nonrestorative Sleep)
  • Breathing Pattern is Associated with Atrial Fibrillation/Flutter, Congestive Heart Failure, or a Neurologic Disorder
  • Disorder is Not Better Explained by Another Current Sleep Disorder, Medication Use, or Substance Use Disorder

Central Sleep Apnea Due to High-Altitude Periodic Breathing

  • Polysomnographic Criteria
    • Recurrent Central Apneas and/or Central Hypopneas Primarily During Non-Rapid Eye Movement (NREM) Sleep at a Frequency of ≥5 Per Hour of Sleep
  • Recent Ascent to High Altitude: typically at least 2500 m, although some individuals may exhibit the disorder at altitudes as low as 1500 m
  • Patient Reports Sleepiness, Awakening with Shortness of Breath, Snoring, Witnessed Apneas, or Insomnia (Difficulty Initiating or Maintaining Sleep, Frequent Awakenings, or Nonrestorative Sleep)
  • Symptoms are Clinically Attributable to High-Altitude Periodic Breathing
  • Disorder is Not Better Explained by Another Current Sleep Disorder, Medical or Neurologic Disorder, Medication Use, or Substance Use Disorder

Central Sleep Apnea Due Medication/Substance

  • Polysomnographic Criteria
    • Study with ≥5 Central Apneas and/or Central Hypopneas Per Hour of Sleep
    • Number of Central Apneas and/or Central Hypopneas is >50% of the Total Number of Apneas and Hypopneas
    • Absence of Cheyne-Stokes Respiration
  • Patient is Taking an Opiate or Other Respiratory Depressant
  • Patient Reports Sleepiness, Awakening with Shortness of Breath, Snoring, Witnessed Apneas, or Insomnia (Difficulty Initiating or Maintaining Sleep, Frequent Awakenings, or Nonrestorative Sleep)
  • Disorder is Not Better Explained by Another Current Sleep Disorder

Clinical Manifestations

Cardiovascular Manifestations

  • Nocturnal Angina (see Chest Pain, [[Chest Pain]])
  • Nocturnal Arrhythmias

Neurologic Manifestations

  • Excessive Daytime Somnolence (see Excessive Daytime Somnolence, [[Excessive Daytime Somnolence]])
  • Fatigue (see Fatigue, [[Fatigue]])
  • Impaired Concentration
  • Insomnia (see Insomnia, [[Insomnia]])
  • Morning Headache (see Headache, [[Headache]])
  • Poor Subjective Sleep Quality
  • Witnessed Hyperpnea/Hypopnea/Apnea During Sleep: may be reported by bed partner

Pulmonary Manifestations

Reproductive Manifestations


Treatment

Primary Central Sleep Apnea

Medications

Oxygen (see Oxygen, [[Oxygen]])

  • May Decrease Respiratory Controller Gain and Stabilize Respiration: however, efficacy of oxygen needs to be determined in a monitored study (with ABG) to assure that it does not worsen respiratory acidosis

Ventilation

  • Continuous Positive Airway Pressure (CPAP) (see Continuous Positive Airway Pressure, [[Continuous Positive Airway Pressure]]): recommended first line ventilation-based treatment (with attended sleep study to determine efficacy)
  • Active Servo Ventilation (ASV) (see Active Servo Ventilation, [[Active Servo Ventilation]]): limited data, second line if CPAP ineffective
  • Bilevel Positive Airway Pressure (BPAP): limited data, second line if CPAP ineffective

Central Sleep Apnea Due to Cheyne-Stokes Respiration in Congestive Heart Failure (CSR-CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])

Opimize Congestive Heart Failure (CHF) Management

  • Standard Measures

Medications

  • Acetazolamide (Diamox) (see Acetazolamide, [[Acetazolamide]])
    • Clinical Efficacy
      • Trial of Acetazolamide in Central Sleep Apnea Associated with Systolic CHF (Am J Respir Crit Care Med, 2006) [MEDLINE]: small trial (n = 12)
        • Acetazolamide Decreased Central Sleep Apneas and Nocturnal Oxygen Desaturation
        • Acetazolamide Improved Sleep Quality, Decreased Daytime Fatigue, and Decreased Daytime Somnolence
      • Short-Term Trial (4 Days) of Acetazolamide in Central Sleep Apnea in Cheyne-Stokes Respiration Due to CHF (Am J Cardiol, 2011) [MEDLINE]: small trial (n = 12)
        • Acetazolamide Decreased Central Sleep Apneas and Nocturnal Oxygen Desaturation
        • Acetazolamide Blunted the Chemosensitivity to Hypoxia and Increased the Chemosensitivity to Hypercapnia
        • In Exercise Testing, Acetazolamide Decreased Workload with No Difference in Peak Oxygen Consumption and an Increment in the Regression Slope Relating Minute Ventilation to Carbon Dioxide Output: suggesting a decrease in ventilatory efficiency
  • Carvedilol (Coreg) (see Carvedilol, [[Carvedilol]])
  • Theophylline (see Theophylline, [[Theophylline]])

Oxygen (see Oxygen, [[Oxygen]])

  • Less Reliably Effective than Ventilation Therapies

Ventilation-Based Therapies

  • Continuous Positive Airway Pressure (CPAP) (see Continuous Positive Airway Pressure, [[Continuous Positive Airway Pressure]])
    • Recommended First Line Ventilation-Based Treatment (with Attended Sleep Study to Determine Efficacy)
    • Note: Auto-Titrating CPAP is Not Recommended for Central Sleep Apnea
    • Clinical Efficacy
      • CANPAP Trial of CPAP in Central Sleep Apnea Associated with Congestive Hart Failure (NEJM, 2005) [MEDLINE]
        • CPAP for Central Sleep Apnea Associated with Congestive Hart Failure Attenuated Central Sleep Apnea, Improved Nocturnal Oxygenation, Increased the Ejection Fraction, Lowered Norepinephrine Levels, and Increased the 6MWT Distance
        • CPAP for Central Sleep Apnea Associated with Congestive Hart Failure Did Not Impact the Mortality Rate
  • Adaptive Servo Ventilation (ASV) (see Active Servo Ventilation, [[Active Servo Ventilation]])
    • SERVE-HF Trial of ASV in CSA Associated with Systolic Congestive Heart Failure (NEJM, 2015) [MEDLINE]
      • ASV Increased the Mortality Rate

Other

  • Atrial Overdrive Pacing
  • Cardiac Resynchronization Therapy (CRT)/b> (see Cardiac Resynchronization Therapy, [[Cardiac Resynchronization Therapy]])
  • Surgery
    • In Patients with CSA Secondary to Congestive Heart Failure from Valvular Disease, Surgical Treatment Has Been Shown to Improve Sleep Disordered Breathing
  • Cardiac Transplant (see Cardiac Transplant, [[Cardiac Transplant]])
    • Although it May be Improved, Cheyne-Stokes Respiration May Persist Post-Cardiac Transplant

Central Sleep Apnea Due to High-Altitude Periodic Breathing (see High Altitude, [[High Altitude]])

Slow Ascent to Altitude

  • May Decrease the Brisk Respiratory Drive Triggered by Hypoxia, Allowing Some Degree of Physiologic Adaptation

Medications

  • Acetazolamide (Diamox) (see Acetazolamide, [[Acetazolamide]]): limited data
  • Temazepam (Restoril, Normison) (see Temazepam, [[Temazepam]])
  • Theophylline (see Theophylline, [[Theophylline]]): limited data

Oxygen (see Oxygen, [[Oxygen]])

  • Can Eliminate Hypoxia, Decreasing Respiratory Drive and Ensuing Central Apneas

Central Sleep Apnea Due to Opiates (see Opiates, [[Opiates]])

Ventilation

  • Continuous Positive Airway Pressure (CPAP) (see Continuous Positive Airway Pressure, [[Continuous Positive Airway Pressure]]): may reduce the apnea-hypopnea index, but frequently does not result in effective control of sleep-disordered breathing (attended sleep study is required to determine effectiveness)
  • Active Servo Ventilation (ASV) (see Active Servo Ventilation, [[Active Servo Ventilation]]): controversial (attended sleep study is required to determine effectiveness)

Alveolar Hypoventilation Due to Neuromuscular Disease/Chest Wall Disorders

Oxygen (see Oxygen, [[Oxygen]])

  • Limited Only to Cases of Alveolar Hypoventilation with Persistent Hypoxemia Despite Control of Hypercapnia with Ventilation

Ventilation

  • General Comments: first line therapy
  • Bilevel Positive Airway Pressure (BPAP) (see Bilevel Positive Airway Pressure, [[Bilevel Positive Airway Pressure]])
    • BPAP-ST Improves Survival and Quality of Life
  • Average Volume Assured Pressure Support (VAPS) (see Volume Assured Pressure Support, [[Volume Assured Pressure Support]]): may be alternative to BPAP-ST, due to its ability to self-adjust pressures to preserve ventilation during disease progression

Alveolar Hypoventilation Due to Obesity Hypoventilation Syndrome (see Obesity Hypoventilation Syndrome, [[Obesity Hypoventilation Syndrome]])

General Measures

  • Weight Loss: bariatric surgery may be required in some cases
    • Weight Loss May Improve Hypoventilation, But OSA Often Persists (Requiring Ongoing Positive Pressure Ventilation Therapy)

Oxygen (see Oxygen, [[Oxygen]])

  • Indications: alveolar hypoventilation with persistent hypoxemia, despite control of hypercapnia with ventilation

Ventilation

  • Continuous Positive Airway Pressure (CPAP) (see Continuous Positive Airway Pressure, [[Continuous Positive Airway Pressure]]): first line therapy
  • Bilevel Positive Airway Pressure (BPAP) (see Bilevel Positive Airway Pressure, [[Bilevel Positive Airway Pressure]]): improves ABG and sleep architecture
    • BPAP May Improve Mortality, But Further Randomized Trials are Required
    • BPAP-ST or BPAP-S
  • Average Volume Assured Pressure Support (VAPS) (see Volume Assured Pressure Support, [[Volume Assured Pressure Support]]): limited data

Tracheostomy (see Tracheostomy, [[Tracheostomy]])

  • Indications: need for long-term mechanical ventilation (in cases where non-invasive ventilation is not successful)

Management of Treatment-Emergent Central Sleep Apnea (Complex Sleep Apnea) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]])

  • May Resolve Over Time in Some Cases: should reassess patient on CPAP in 2-3 mo
    • Complex Sleep Apnea Resolution Study (Sleep, 2014) [MEDLINE]: central sleep apnea improves or resolves spontaneously in approximately 66% of patients who continue on CPAP for 90 days
  • Adaptive Servo Ventilation (ASV) (see Adaptive Servo Ventilation, [[Adaptive Servo Ventilation]]): may be useful, as it treats both obstructive and central apneas
    • ASV is a form of bi-level positive airway pressure that provides variable pressure support via a servo mechanism-based assessment of the patient’s respiratory output
    • When There are Hypopneas: ASV increases the pressure support (difference between expiratory PAP and inspiratory PAP)
    • When There are Hyperpneas: ASV decreases the pressure support (difference between expiratory PAP and inspiratory PAP)
    • When Central Sleep Apneas Occur: ASV utilizes a backup rate and the EPAP maintains airway patency
    • ASV increases the mortality rate in patients with central sleep apnea in association with systolic congestive heart failure and EF <45% (NEJM, 2015) [MEDLINE]
  • Bilevel Positive Airway Pressure (BPAP) with Backup Rate (see Bilevel Positive Airway Pressure, [[Bilevel Positive Airway Pressure]]): may be used
    • Avoid Using BPAP without a Backup Rate: may worsen the apnea-hypopnea index (AHI)

Prognosis

  • In presence of CSA associated with CHF, the CHF is typically more severe (with higher PCWP) and has poorer prognosis

References

  • Central sleep apnea in stable methadone treatment patients. Chest 2005; 128: 1348–56 [MEDLINE]
  • Obstructive sleep apnea is more common than central sleep apnea in methadone maintenance patients with subjective sleep complaints. Drug Alcohol Depend. 2010; 108: 77–83 [MEDLINE]
  • Therapy for sleep hypoventilation and central apnea syndromes. Curr Treat Options Neurol 2012;14(5):427-437 [MEDLINE]
  • The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012;35:17–40 [MEDLINE]
  • International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014 Nov;146(5):1387-94. doi: 10.1378/chest.14-0970 [MEDLINE]
  • SERVE-HF Trial. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N Engl J Med. 2015 Sep 17;373(12):1095-105. doi: 10.1056/NEJMoa1506459. Epub 2015 Sep 1 [MEDLINE]
  • Nocturnal oxygen therapy in patients with chronic heart failure and sleep apnea: a systematic review. Sleep Med. 2016 Jan;17:149-57. doi: 10.1016/j.sleep.2015.10.017. Epub 2015 Dec 2 [MEDLINE]