1. Central Sleep Apnea Syndromes 6 th Annual Conference Northwest Ohio Southeast Michigan Sleep Society May 1, 2009 Navin K Jain, MD

2. CENTRAL SLEEP APNEA “ period of at least 10 seconds without airflow, during which no ventilatory effort is evident”

3. Normal Control of Breathing Automatic / Metabolic  Chemoreceptors (carotid body for hypoxia and carotid body and medullary receptors for hypercapnia and H ion)  Intrapulmonary receptors – vagus mediated  Brainstem processes  Keep ventilation regular and match to metabolic demands Afferent Information from chest wall and respiratory muscles Behavioral / Volitional – under voluntary control Wakefulness stimulus – increased ventilation in awake state (ventilation persist during wakefulness in absence of metabolic mechanisms)

4. Control of Breathing at Sleep/Wake Transition to Sleep  Loss of wakefulness stimulus and behavioral influences  Muscle activity and chemoreceptor sensitivity is reduced Apnea threshold Stable sleep changes – sleep specific CO2 set point Transition to Wake - important to restore gas exchange; may cause central apnea:  Arousal threshold  Ventilatory Response to arousal

5. Control Of Breathing in Sleep Non REM Sleep  Metabolic Control – input from chemoreceptors and vagal intrapulmonary receptors (oxygen administration in hypoxic individuals reduces ventilation and may prolong apneas in some individuals; hypocapnic alkalosis also reduces ventilation)  Response of chemoreceptors are somewhat reduced in Non REM sleep but still well maintained and maintains rhythmic ventilation during sleep REM Sleep – further reduction in responsiveness of chemoreceptors

6. Central Sleep Apnea Lack of drive to breathe during sleep Lack of respiratory efforts during cessation of airflow Insufficient or absent ventilation leading to compromised gas exchange May lead to frequent nighttime awakenings leading to excessive daytime sleepiness and increased risk of adverse CV outcomes Most patients have overlap of OSA and CSA CSA Syndrome is considered primary diagnosis when >50% of apneas are scored as central in origin

8. CSA: Classification Central Sleep Apnea  High Altitude Periodic Breathing  Idiopathic CSA  Narcotic Induced Central Apnea Cheyne Stokes Breathing (CSB) Obesity Hypoventilation Syndrome (OHS) (Hypercapneic CSA) Complex Sleep Apnea

9. CSA Syndrome Hypercapnic – impaired ventilatory output during wakefulness (worsens is sleep as wakefulness stimulus is removed)  Impaired Central Drive  Impaired Respiratory Motor Control Nonhypercapnic  Cheyne Stokes Breathing  Idiopathic CSA

10. Hypercapnic CSA: Impaired Central Drive Lesions of brain stem – tumors, trauma induced lesions Congenital Central Hypoventilation Syndrome (Ondine’s curse) Long term use of Opioids – prolonged periods of hypoventilation with marked hypoxemia and repetitive central apneas; dose dependent effects Obesity Hypoventilation Syndrome (OHS)

11. CSA: Neurologic causes Disorders of autonomic system  Autonomic dysfunction - Shy Drager Syndrome  Familial Dysautonomia  Diabetes Mellitus Damage to Brain Stem (respiratory centers)  Post Polio syndrome  Tumor, Infection, Hemorrhage, encephalitis Interruption of Neural pathways from medullary respiratory centers to ventilatory muscles  Cervical cordotomy

12. Chronic Opioid use Becoming more common for chronic pain (even non malignant disorders) Most experts believe – respiratory tolerance develops and respiratory depression is absent or mild During wakefulness, chronic respiratory acidosis is absent or mild While sleeping, 30-90% patients will have sleep apnea (central or obstructive) – may contribute to mortality

13. Obesity Hypoventilation Syndrome Obesity – BMI > 35 Alveolar Hypoventilation (PaCO2 >45 mm Hg) while awake Hypoventilation worsens during non-REM sleep and further during REM sleep Other causes of hypoventilation have been ruled out  COPD, Interstitial Lung Disease  Chest Wall Disease – Kyphoscoliosis  Hypothyroidism  Heart failure  Diaphragm Paralysis

14. Hypercapnic CSA: Impaired Respiratory Motor Control Neuromuscular Disorders  Myasthenia Gravis  ALS  Post Polio Syndrome  Myopathies Chest wall syndromes  Kyphoscoliosis

15. Nonhypercapnic CSA CSB Idiopathic CSA

16. Cheyne-Stokes Breathing (CSB) Cyclic crescendo-decrescendo respiratory effort and airflow during wakefulness and sleep, without upper airway obstruction

17. Idiopathic CSA Do not show CSB / transition apnea with normocapnia May occur as distinct events or repetitive cyclical pattern Duration of cycle – usually 20-40 seconds; less severe O2 desaturations Mainly in stage N1 and N2 sleep Arousals at termination of apnea May complain of insomnia or hypersomnia Usually have elevated hypercapnic ventilatory response

18. High Altitude Periodic Breathing Most healthy individuals will have periodic breathing on high altitude ascent provide ascent causes significant alveolar hypoxia

19. Factors affecting CSA severity Hypoxia  Any hypoxia tends to worsen CSA severity  More severe hypoxia seen in OHS; mild in idiopathic CSA and OHS  Hypoxia may impair respiratory sensory feedback Upper Airway Anatomy  Narrow upper airway can collapse in central apnea (as it depends on neuronal input)  Treatment of OSA with PAP may cause hypocapnia in patients and may cause treatment emergent CSA by causing hypercapnia (Complex Sleep Apnea)

20. Cheyne Stokes Breathing (CSB)

21. Cheyne-Stokes Breathing (CSB) Cyclic crescendo-decrescendo respiratory effort and airflow during wakefulness and sleep, without upper airway obstruction If decrescendo effort is accompanied by apnea during sleep, it is a type of central sleep apnea syndrome Mainly seen is stage N1 and N2 sleep Cycle time – 60-90 seconds (longer than other forms of CSA); correlation with severity of HF Arousal typically occurs mid cycle at peak of ventilatory effort Most commonly seen in patients with CHF and LV systolic dysfunction Often co-exist with OSA (together may be classified as Sleep Disordered Breathing)

23. CSB: Pathogenesis Uncertain Seen as series of events  Patients are hypocapnic to begin with, so to correct hypocapnia, respiratory center initiates an apnea; pCO2 begins to rise.  Duration from beginning of apnea until respiratory center detects increasing PaCO2 is prolonged due to increased circulatory time  When respiratory center terminates apnea, it is already hypercapnia  Hypercapnia causes hyperpnea which causes hypocapnia NET EFFECT – oscillation of ventilation between apnea and hyperpnea Elimination of hypocapnia with inhaled CO2, CPAP or O2 can attenuate CSB

24. Factors contributing to CSB High ventilatory drive Minimal difference between apnea threshold and sleeping eucapnic PaCO2 Long circulation time Impaired cerebrovascular reactivity to CO2 Increase pulmonary capillary wedge pressure may stimulate J receptors in lung causing apnea and resultant hyperventilation

25. Sleep Disordered Breathing (SDB) in Heart Failure SDB may be seen in ~50% all patients with heart failure and ~70% patients with heart failure who are referred to sleep laboratory Can be seen among patients whose heart failure is optimally managed CSB may be more common than OSA in patients with heart failure CSB more common among men, elderly, atrial fibrillation, and hypocapnia OSA more common among older individuals and increasing BMI

26. CSB: Effects Intermittent hypoxia – increased sympathetic drive causing arhythmia and worsening of HF Arousals – induce adrenergic surges Impair systolic and diastolic function Extremely negative intrapleural pressure with hyperpnea increase ventricular transmural wall stress and afterload CSB in patients with heart failure is associated with higher cardiac mortality Clinically  Poor sleep quality – sleepiness in daytime  Symptoms of worsening heart failure – dyspnea, edema  Paroxysmal nocturnal dyspnea (due to hyperpnea)  Nocturnal angina, recurrent arrhythmia

27. CSB : Treatment Management of CHF Supplemental Oxygen Acetazolamide Theophylline Pacemaker Heart Transplantation PAP therapy

28. Narcotic Induced CSA

29. Chronic Opioid use : CSA / CompSA While sleeping, 30-90% patients on chronic opioids will have sleep apnea (central or obstructive) – may contribute to mortality Acute uses – case report Chest 2008 (nightly dose) low AHI high sleep efficiency Disproportionate symptoms (excess daytime sleepiness

30. CSA in Chronic Opioid Users Develop combination of obstructive and central apnea events (pathogenesis – unknown)  Central events mainly in Non REM sleep  With PAP therapy, on CPAP obstructive events may be corrected and central events persist  When compared to age, gender, and BMI matched controls, higher AHI is due to central events  Dose relationship noted with AHI and dose of opioid Central Apnea events Periods of apnea and hyperepnea (Biot’s respiration) Breaths at end of apnea are abrupt and not gradual Irregular; erratic pattern of respiratory rate and tidal volume

31. CSA in Chronic Opioid Users Central Apnea events Periods of apnea and hyperepnea (Biot’s respiration) Breaths at end of apnea are abrupt and not gradual Irregular; erratic pattern of respiratory rate and tidal volume

32. Biot’s Respiration

33. Narcotic Induced CSA: Treatment Minimize dose of Narcotics PAP therapy  CPAP – alone not effective  Usually require APSSV

34. Obesity Hypoventilation Syndrome (OHS)

35. Pickwick Papers

36. Obesity Hypoventilation Syndrome Obesity – BMI > 35 Alveolar Hypoventilation (PaCO2 >45 mm Hg) Hypoventilation worsens during non-REM sleep and further during REM sleep Other causes of hypoventilation have been ruled out  COPD, Interstitial Lung Disease  Chest Wall Disease – Kyphoscoliosis  Hypothyroidism  Heart failure  Diaphragm Paralysis

37. OHS: clinical features Symptoms similar to OSA  Loud snoring, periods of choking in sleep, excessive sleepiness in daytime, fatigue Dyspnea on exertion BMI >35 kg/m2 May heave features of Right Heart Failure  Rales, hepatomegaly, edema Hypercapnia – PaCO2>45 mm Hg during wakefulness Hypoxic – PaO2 <70 mm Hg but have normal alveolar-arterial gradient if no associated heart or lung disease Elevated hematocrit EKG, ECHO – features of RVH, Pulmonary HTN PFT – restrictive ventilatory defect Often have coexisting OSA

38. OHS: Pathogenesis Obesity Related Physiologic abnormalities OSA Increased work of breathing – due to reduced lung compliance and increased effort to move ribs and diaphragm Respiratory Muscle Impairment - Depressed Central Ventilatory Drive – reduced response to chemostimuli – hypoxia and hypercapnia (it may be effect of OHS rather than cause) V/Q mismatching – poor ventilation of lower lobes and increased perfusion to lower lobes Diminished effects of neurohumoral modulators (leptin) due to reduce levels or resistance Weight Loss alone can cause decrease in PaCO2 during wakefulness in these patients

39. OHS and sleep study Oxygen desaturation during sleep  Occur for longer periods than in patients who have OSA alone Most patients have associated OSA AHI severity is not associated with likelihood of coexisting OHS but severe oxygen desaturation is associated with coexisting OHS

41. OHS: Treatment Weight Loss Respiratory Stimulants  Progesterone PAP therapy Oxygen Phlebotomy

42. Treatment Emergent CSA Complex Sleep Apnea (CompSA)

43. Described by Morgenthaler; Sleep2006 29:1203-09 Treatment emergent central sleep apnea Persistence or emergence of central apneas or hypopneas upon exposure to CPAP or an E0470 device when obstructive events have disappeared Controversial – is it really a disease

44. CompSA: A Disease Patients have anatomic and physiologic vulnerability causing OSA and a central breathing control instability Seen more among men Less sleep maintenance insomnia complaint Higher likelihood of CHF or ischemic heart disease Is it transient or persist if treated with CPAP alone

45. CompSA: Not a Disease Transient and disappear with CPAP therapy in most patients Relief of upper airway obstruction may cause change in CO2 excretion (so PaCO2 falls below apnea threshold) Over titration  Activation of lung stretch receptors inhibits central respiratory motor input  Washout of CO2 from anatomic dead space Increased transitions from sleep to wake as getting used to PAP – CPAP initiation may worsen sleep quality

47. BPAP Titration

48. BPAP - Timed

49. Adapt PS Servo Ventilation

50. PAP therapy Continuous PAP (CPAP)  Useful in OSA  Useful in CSA with systolic heart failure Bi-level PAP (BPAP) Bi-level PAP with timed mode (BPAP S/T) Adaptive Pressure Support Servo Ventilation (APSSV)  Used in patients with CSA, treatment emergent CSA, CSB

51. APSSV Expiratory Pressure is set to eliminate obstructive apneas Inspiratory support (variable) above expiratory pressure – provided by breath-breath analysis Back Up Rate – aborts any impending central apnea Some times may not work as well in patients with chronic opioid therapy (may not regulate irregular breathing)

52. Diagnosis of CSA No screening tool – like apnea link Main test - Polysomnogram