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
    • Methadone (see Methadone, [[Methadone]])

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
    • Idiopathic Pulmonary Fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis, [[Idiopathic Pulmonary Fibrosis]])
  • 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

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

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

• Paroxysmal Nocturnal Dyspnea (PND) (see Paroxysmal Nocturnal Dyspnea, [[Paroxysmal Nocturnal Dyspnea]])

Reproductive Manifestations

• Decreased Libido (see Decreased Libido)
• Impotence (see Impotence )

Primary Central Sleep Apnea

Medications

• Acetazolamide (Diamox) (see Acetazolamide)
• Triazolam (Halcion) (see Triazolam)
• Zolpidem (Ambien) (see Zolpidem)

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