1. Respiratory Physiology In Sleep Ritu Grewal, MD

2. States of Mammalian Being Wake Non-REM sleep –brain is regulating bodily functions in a movable body REM sleep: -highly activated brain in a paralyzed body

3. Electrographic State Determination Wake NREM REM EEG - Desynchronized EMG - Variable EEG - Synchronized EMG - Attenuated but present EEG - Desynchronized EMG - Absent (active paralysis)

4. Normal Sleep Histogram

5. Rapid eye movements Mixed frequency EEG Low tonic submental EMG Stage REM

6. Overview of Sleep and Respiratory Physiology I. CNS Ventilatory Control II. Respiratory Control of the Upper Airway III. Obstructive Sleep Apnea

7. Ventilatory pump and its central neural control

8.  Dorsal view of the brainstem and upper spinal cord showing the medullary origin of the descending inspiratory and expiratory pathways that control major respiratory pump muscles, such as the diaphragm and intercostals.  Central respiratory neurons form a network that ensures reciprocal activation and inhibition among the cells to be active during different phases of the respiratory cycle.  Respiratory-modulated cells in the pons integrate many peripheral and central respiratory and non-respiratory inputs and modulate the cells of the medullary rhythm and pattern generator. Main pontomedullary respiratory neurons

9. Influences on Respiration in Wake State Metabolic control /Automatic control –Maintain blood gases Voluntary control/behavioral –Phonation, swallowing (wakefulness stimulus to breathing)

10. Respiration during sleep Metabolic control/automatic control –Controlled by the medulla on the respiratory muscles –Maintain pCO2 and pO2

12. Changes in Ventilation in sleep Decrease in Minute Ventilation (Ve)(0.5-1.5 l/min)Decrease in Minute Ventilation (Ve)(0.5-1.5 l/min) Decrease in Tidal Volume)Decrease in Tidal Volume) Respiratory Rate unchangedRespiratory Rate unchanged ↑ UA resistance (reduced activity of pharyngeal dilator muscle activity)↑ UA resistance (reduced activity of pharyngeal dilator muscle activity) Reduction of VCO2 and VO2 (reduced metabolism)Reduction of VCO2 and VO2 (reduced metabolism) Absence of the tonic influences of wakefulnessAbsence of the tonic influences of wakefulness Reduced chemosensitivityReduced chemosensitivity

13. Changes in Blood Bases Decrease in CO2 production (less than decrease in Ve)Decrease in CO2 production (less than decrease in Ve) Increase in pCO2 3-5 mm HgIncrease in pCO2 3-5 mm Hg Decrease in pO2 by 5-8 mm HgDecrease in pO2 by 5-8 mm Hg O2 saturation decreases by less than 2%O2 saturation decreases by less than 2%

14. Chemosensitivity and Sleep

16. Metabolism Metabolism slows at sleep onsetMetabolism slows at sleep onset Increases during the early hours of the morning when REM sleep is at its maximumIncreases during the early hours of the morning when REM sleep is at its maximum Ventilation is worse in REM sleepVentilation is worse in REM sleep

17. REM sleep Worse in REM sleepWorse in REM sleep Hypotonia of Intercostal muscles and accessory muscles of respirationHypotonia of Intercostal muscles and accessory muscles of respiration Increased upper airway resistanceIncreased upper airway resistance Diaphragm is preservedDiaphragm is preserved Breathing rate is erraticBreathing rate is erratic

18. Arousal responses in sleep Reduced in REM compared to NonREMReduced in REM compared to NonREM Hypercapnia is a stronger stimulus to arousal than hypoxemiaHypercapnia is a stronger stimulus to arousal than hypoxemia –Increase in pCO2 of 6-15 mmHg causes arousal –SaO2 has to decrease to below 75% Cough reflex in response to laryngeal stimulation reduced (aspiration)Cough reflex in response to laryngeal stimulation reduced (aspiration)

19. Overview of Sleep and Respiratory Physiology I. CNS Ventilatory Control II. Respiratory Control of the Upper Airway III. Obstructive Sleep Apnea

20. Anatomy of the Upper Airway The Upper Airway is a Continuation of the Respiratory System 20

21. The Upper Airway is a Multipurpose Passage It transmits air, liquids and solids. It is a common pathway for respiratory, digestive and phonation functions. 21

22. Collapsible Pharynx Challenges the Respiratory System Airflow requires a patent upper airway. Nose vs. mouth breathing must be regulated. State of consciousness is a major determinant of pharyngeal patency. 22

23. Components of the Upper Airway Nose Nasopharynx Oropharynx Laryngopharynx Larynx 23

24. Anatomy of the Upper Airway Alae nasi (widens nares) Levator palatini (elevates palate) Tensor palatini (stiffens palate) 24

25. Anatomy of the Upper Airway Genioglossus (protrudes tongue) Geniohyoid (displaces hyoid arch anterior) Sternohyoid (displaces hyoid arch anterior) Pharyngeal constrictors (form lateral pharyngeal walls) 25

26. Pharyngeal Muscles are Activated during Breathing Mechanical Properties and Collapsibility of Upper Airway Reflexes Maintaining an Open Airway and Effects of Sleep Respiratory Control of the Upper Airway

27. Upper airway muscles modulate airflow 1.Primary Respiratory Muscles (e.g., Diaphragm, Intercostals) Contraction generates airflow into lungs 2.Secondary Respiratory Muscles (e.g., Genioglossus of tongue) Contraction does not generate airflow but modulates resistance Upper Airway (collapsible tube) Respiratory Pump Respiratory pump muscles generate airflow

28. Awake Genioglossus +++ Intercostals +++ Diaphragm +++ Non-REM ++ REM ++ + + Consequences:  Lung ventilation in sleep caused by both  Upper airway resistance (major contributor) and  pump muscle activity Clinical Relevance: Airway narrowing in sleep (potential for hypopneas and obstructions) Sleep reduces upper airway muscle activity more than diaphragm activity Sleep and respiratory muscle activity

29. The pharynx is a collapsible tube vulnerable to closure in sleep – especially when supine Tendency for Airway Collapse : Reduced muscle activation in sleep Weight of tongue Weight of neck - worse with obesity Worse when supine + Diaphragm ++ Sleep Genioglossus Diaphragm +++ Awake Tongue movement Clinical Relevance: Snoring Airflow limitation (hypopneas) Obstructive Sleep Apnea (OSA) Tendency for upper airway collapse in sleep

30. Tonic and respiratory inputs summate to determine pharyngeal muscle activity Genioglossus muscle: Respiratory-related activity superimposed upon background tonic activity Tensor veli palatini (palatal muscle): Mainly tonic activity Enhances stiffness in the airspace behind the palate Determinants of pharyngeal muscle activity

31. Pharyngeal Muscles are Activated during Breathing Mechanical Properties and Collapsibility of Upper Airway Reflexes Maintaining an Open Airway and Effects of Sleep Overview of Sleep and Respiratory Physiology

32. The airway is narrowest in the region posterior to the soft palate Retropalatal Airspace Glossopharyngeal Airspace Airway anatomy and vulnerability to closure Redrawn from Horner et al., Eur Resp J, 1989

33. Retropalatal Airspace Glossopharyngeal Airspace Normal OSA Inspiration Expiration The upper airway is: (1) Narrowest in the retropalatal airspace (2) Narrower in obstructive sleep apnea (OSA) patients vs. controls (3) Varies during the breathing cycle (narrowest at end-expiration) Upper airway size varies with the breathing cycle Redrawn from Schwab, Am Rev Respir Dis, 1993

34. The upper airway is narrowest at end-expiration and so vulnerable to collapse on inspiration Upper airway at end-expiration is most vulnerable to collapse on inspiration Tonic muscle activity sets baseline airway size and stiffness (  in sleep) Any factor that  airway size makes the airway more vulnerable to collapse Retropalatal Airspace Glossopharyngeal Airspace Normal OSA Upper airway size varies with the breathing cycle Redrawn from Schwab et al., Am Rev Respir Dis, 1993

35. OSA patients have larger retropalatal fat deposits and narrower airways Fat deposit Magnetic resonance image showing large fat deposits lateral to the airspace These fat deposits are larger in OSA patients compared to weight matched controls Weight loss decreases size of fat deposits and increases airway size Retropalatal airspace Fat deposits around the upper airspace From Horner, Personal data archive

36. Mechanics of the upper airway and influences on collapsibility The upper airway has been modeled as a collapsible tube with maximum flow (V MAX ) determined by upstream nasal pressure (P N ) and resistance (R N ). ● P N (cmH 2 O) 0 100 200 300 400 500 0 4 8-4 -8 P CRIT R N = 1/slope V MAX (ml/sec) ● Airflow ceases in the collapsible segment of the upper airway at a value of critical pressure (P CRIT ). V MAX is determined by: V MAX = (P N - P CRIT ) / R N ● ● Lungs PNPN RNRN P CRIT V MAX ● Determinants of upper airway collapsibility Redrawn from Smith and Schwartz, Sleep Apnea: Pathogenesis, Diagnosis and Treatment, 2002

37. Mechanics of the upper airway influences airway collapsibility P N (cmH 2 O) V MAX (ml/sec) 0 500 15 0 10 5 -5 -10 -15 Normal Snorer Hypopnea OSA ● P N (cmH 2 O) V MAX (ml/sec) 0 100 200 300 400 500 0 4 8-4 -8 Passive Upper Airway Active Upper Airway  P CRIT  V MAX ● ● P CRIT is more positive (more collapsible airway) from groups of normal subjects, to snorers, and patients with hypopneas and obstructive sleep apnea (OSA). Increases in pharyngeal muscle activity (passive to active upper airway) increase V MAX and decrease P CRIT, i.e., make the airway less collapsible. ● Influences on upper airway collapsibility Redrawn from Smith and Schwartz, Sleep Apnea: Pathogenesis, Diagnosis and Treatment, 2002

38. Pharyngeal Muscles are Activated during Breathing Mechanical Properties and Collapsibility of Upper Airway Reflexes Maintaining an Open Airway and Effects of Sleep Overview of Sleep and Respiratory Physiology

39. Sub-atmospheric airway pressures cause reflex pharyngeal muscle activation Sub-atmospheric airway pressures cause short latency (reflex) genioglossus muscle activation in humans Reflex thought to protect the upper airway from suction collapse during inspiration Reflex is reduced in non-REM sleep and inhibited in REM sleep Genioglossus Electromyogram Suction Pressure (cmH 2 O) 0 -25 100 msec Reflex responses to sub-atmospheric pressure From Horner, Personal data archive

40. Major contribution of nasal and laryngeal afferents to negative pressure reflex in humans 0 Genioglossus Electromyogram Suction Pressure (cmH 2 O) -25 100 msec Normal response Anesthesia of nasal afferents Anesthesia of laryngeal afferents Afferents mediating reflex response From Horner, Personal data archive

41. Upper airway trauma may impair responses to negative pressure and predispose to OSA Sleeping normal subject Narrower than normal airway Structural (e.g., obesity, position)  muscle activity (e.g., alcohol) Exaggerated negative airway pressure Reflex pharyngeal dilator muscle activation (e.g., genioglossus) Small responder Big responder Snoring, hypopneas and occasional OSA Decrement in upper airway mucosal sensation to pressure Decrement in upper airway reflex Worsening snoring and OSA Any decrement in reflex e.g., age, alcohol No change in reflex Remain normal Upper airway reflex and clinical relevance Redrawn from Horner, Sleep, 1996

42. Chemoreceptor stimulation cause reflex pharyngeal muscle activation Wakefulness Non-REM sleep REM sleep Respiratory-Related Genioglossus Activity (mV) Inspired CO2 (%) Chemoreceptor stimulation increases genioglossus muscle activity Reflex is reduced in sleep, especially REM sleep Responses to hypercapnia in sleep Modified from Horner, J Appl Physiol, 2002

43. Overview of Sleep and Respiratory Physiology I. CNS Ventilatory Control II. Respiratory Control of the Upper Airway III. Obstructive Sleep Apnea

44. Obstructive Sleep Apnea (OSA) Syndrome Very common; affects 2-5% of middle-aged persons, both men and women. The initial cause is a narrow and collapsible upper airway (due to fat deposits, predisposing cranial bony structure and/or hypertrophy of soft tissues surrounding the upper airway). State-dependent respiratory disorders - OSA

45. OSA patients have adequate ventilation during wakefulness because they develop a compensatory increase in the activity of their upper airway dilating muscles (e.g., contraction of the genioglossus, the main muscle of the tongue, effectively protects against upper airway collapse). However, the compensation is only partially preserved during SWS and absent during REMS. This causes repeated nocturnal upper airway obstructions which in most cases require awakening to resolve. State-dependent respiratory disorders - OSA

46. OSA is characterized by cessation of oro-nasal airflow in the presence of attempted (but ineffective) respiratory efforts and is caused by upper airway closure in sleep Hypopneas are caused by reductions in inspiratory airflow due to elevated upper airway resistance Polysomnographic tracings in OSA Redrawn from Thompson et al., Adv Physiol Educ, 2001

47. The site of obstruction varies within and between patients with obstructive sleep apnea All patients obstruct at level of soft palate ~50% of patients: obstruction behind tongue in non-REM REM: Obstruction extends caudally Site of obstruction in OSA

48. In severe OSA, 40-60 episodes of airway obstruction and subsequent awaking occur per hour; due to overwhelming sleepiness, the patient is often unaware of the nature of the problem. In light OSA, loud snoring is associated with periods of hypoventilation due to excessive airway narrowing. State-dependent respiratory disorders - OSA

49. Sleep loss, sleep fragmentation and recurring decrements of blood oxygen levels (intermittent hypoxia) have multiple adverse consequences for cognitive and affective functions, regulation of arterial blood pressure (hypertension), and metabolic regulation (insulin resistance, hyperlipidemia). State-dependent respiratory disorders - OSA

50. Summary Increased upper airway resistance-OSASIncreased upper airway resistance-OSAS Circadian changes in airway muscle toneCircadian changes in airway muscle tone Reduced ventilationReduced ventilation –COPD –Neuromuscular diseases –Interstitial lung disease

51. COPD Hyperinflated diaphragm(reduced efficiency)Hyperinflated diaphragm(reduced efficiency) ABG’s deteriorate during sleepABG’s deteriorate during sleep Coexisting OSAS-severe hypoxemiaCoexisting OSAS-severe hypoxemia Pulmonary hypertensionPulmonary hypertension

52. Decreased ventilatory responses to hypoxia, hypercapnia, and inspiratory resistance during sleep, particularly in REM sleep, permit REM hypoxemia in patients with chronic obstructive pulmonary disease, chest wall disease, and neuromuscular abnormalities affecting the respiratory muscles. They may also contribute to the development of the sleep apnea/hypopnea syndrome.

53. CNS Ventilatory Control – Summary 1 The respiratory rhythm and pattern are generated centrally and modulated by a host of respiratory reflexes. The basic respiratory rhythm is generated by a network of pontomedullary neurons, of which some have pacemaker properties. The central controller is set to ensure ventilation that adequately meets demand for O 2 supply and CO 2 removal.

54. CNS Ventilatory Control – Summary 2 Pharyngeal muscles are activated during breathing Upper airway size varies during breathing Mechanical properties of the upper airway influences collapsibility Reflexes modulate pharyngeal muscle activity, but reflexes are reduced in sleep These mechanisms contribute to normal maintenance of airway patency and are relevant to obstructive sleep apnea